[intro music]

 

Hello, and welcome to Episode Twenty-Five of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features a special interview with actor and science advocate, Alan Alda, whom you may remember as Hawkeye Pierce in M*A*S*H. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

Positive thinking may lead to positive clinical outcomes, according to a new meta-analysis. The investigators found that interventions such as cognitive behavioral therapy helped patients deal with physical symptoms like fatigue and pain. They suggested that psychological well-being should be assessed and treated along with physical disability in people with MS. The researchers also called for studies that examined the connection between the psychological and the physical more directly.

 

Moving from the macro to the micro, we recently published an article about axonal transport. Axons rely on motor proteins to carry cargo across long tracks of microtubules in order to survive. A disruption in this process is associated with neurodegeneration. Recently a team of researchers discovered that axonal transport is disrupted in mice with EAE. In this animal model of MS, even normal-appearing axons failed to transport organelles as quickly or as effectively as healthy axons. But the researchers were able to reverse the process, suggesting a potential new therapeutic target for drug development.

 

[transition music]

 

Now to the interview. Alan Alda is an actor known for his television roles in M*A*S*H and The West Wing. But he’s also a longtime advocate of science and scientific literacy and the founder of the Alan Alda Center for Communicating Science at Stony Brook University. He met with MSDF recently to talk about the art of good science communication.

 

[Interview]

 

Interviewer – Dan Keller

What, at this point, would you say are the one or two biggest pieces of advice you could give to any technical person or a scientist trying to get his point across to the general public?

 

Interviewee – Alan Alda

I think the most important thing to remember is that it’s not nearly so important to worry about what you have to say to the other person, as it is to think about how the other person is receiving what you have to say. We know this intellectually because everybody knows that you want to know your audience, everybody knows you want to start where the student is, you know, find out what they know and build on that, that kind of thing. We all know that.

 

But one of the things that I think that we’ve found at the Center for Communicating Science that I helped start is that you need to get in the habit of doing that; you need to really go through the experience of actually opening up to other people, getting their feedback, being able to read from the signals that they give you on their face and their body language – all the various signals you can get – whether or not they’re really paying attention and really following you. If you miss one of the crucial words I say at the beginning of a paragraph, the rest of the paragraph is dead; you’re spending most of your time trying to figure out what I’m talking about.

 

MSDF

As an example, say, in Scientific American Frontiers, you elicited great storytelling; I mean, I assume part of that was picking the right speakers, but how do you coax it out of them in an understandable way? I mean can you essentially guide people without saying, “Hey, come on, bring it down, bring it down.”?

 

Mr. Alda

I think Scientific American Frontiers worked as well as it did because in a way it was a rare thing – I hadn’t seen it done before and so maybe it has, but I hadn’t seen it – where you had a naïve person – ignorant, played by me – and I wasn’t acting. I made use of the natural fund of ignorance that I came in with. I didn’t aspire to an ignorance I didn’t possess, it was real; I really didn’t know what these people did in the laboratory, and I really did want to know what it was. And I wanted to understand it, so I badgered them until I understood it, and I didn’t pretend I understood it if I didn’t. That step where they actually had to come to terms with this person standing right next to them looking up in their faces where they had to actually make it clear to this one person, that changed them in some way, that brought out the human being in them. And they forgot about the camera, they forgot about the millions of people that they might have gone into lecture mode to explain this to. They were talking to one individual and that made a big difference, because they became much more human.

 

So, yeah, I think that we had people who were comfortable being in front of a camera, but regardless of how comfortable they were in making their language plain-spoken, they had to get even more so when they talked to me because I really, I just tugged at their coat until I understood it. And something happened between us, there was some kind of connection between us that was very watchable, very interesting. I think that helped draw other people in. After we did that, I really wondered if a scientist didn’t have this person dogging him or her to get the information out, but to get it out understandably, what would do it? How could they get accustomed to speaking as though they’re talking to another person who really wants to know? And that’s when it occurred to me that I bet we could teach them improvising and that would help them get more personal, and it has.

 

 

MSDF

To envision one person.

 

Mr. Alda

Well, when you improvise, at least the way we improvise with scientists, it’s not for the purpose of getting them to be comical, or to make things up on the spot, or to be clever. The whole thing is designed to get the scientists to be accustomed to observing the person they’re talking to, because you can’t play these improvising games unless you’re tuned into the other person in a very powerful way. Once they get used to that and when they turn and talk to an audience, they carry with them that same ability to talk to the people and not over their heads and not at them. They don’t spray information at them anymore, they actually engage the audience, and that’s a tremendous difference.

 

MSDF

Let me switch gears a little bit. I don’t know if you’ve ever noticed it, I’ve certainly noticed it, between different closely related scientific disciplines – I mean, I cover medicine mostly – and people in just very closely related things, there’s no cross-pollination. They’re surprised when they hear something that’s going on. Oh, you know, that could be applicable to me. And I think there’s even a lack of communication between the disciplines between scientists. They can certainly speak in the same jargon, but I don’t know if there’s a barrier or if they’re just so wrapped up in their own stuff.

 

Mr. Alda

It seems to be a really serious problem that scientists need more and more to collaborate across disciplines, and the problem is that they often – I think I could say often – don’t understand one another much better than a layperson understands a scientist in a specialized field. So at a certain level, at a certain distance from one another’s work, they’re really in the position of an interested layperson rather than a collaborator, rather than a colleague. And we have to bridge that gap if we’re going to get the benefits of collaboration. And I’ve heard some horror stories of scientists getting together and not understanding one another. And on the other hand, I’ve heard these really heartbreakingly wonderful stories.

 

When we have a workshop with a range of scientists, scientists from several different fields, one of the wonderful things they say is this has been great, I got to understand, I got to hear about this guy’s work and I never knew anything about it before. They’re hearing an explanation of another person’s work in terms that they might say it to the lay public. It’s acceptable to the other scientists because we don’t ask them to dumb it down, we ask them NOT to dumb it down just to make it clear. So they’re getting a clear version of somebody else’s work that doesn’t include the jargon of that specialized field. It’s stripped of its jargon, it’s spoken in plain language. And the emotion, the passion that the scientist feels about it is allowed to come out because that’s part of the human story that science is. Science, rather than being passionless, is generated by passion. So it’s great that that comes out in this work.

 

 

MSDF

In the training, obviously you can tell if there’s a difference between before and after. But have you ever been able to test the durability of this, that these people retaining these? Or do they lapse back? Or can you tell?

 

Mr. Alda

It’s hard to get measurements on the success of this, but we’re beginning to get some early results because we’ve been working with teaching assistants. And teaching assistants are graduate students who are asked to give courses to undergraduates to see if the undergraduates want to go into science. And one of the problems has been that a lot of them drop out because they can’t get interested in the science partly because the teaching assistants don’t have any training in communication or in education; they know the material but they’re not really experienced at communicating. So we put them through a course of communication, and then we find some of the numbers we’re getting back are that the students are rating them as highly or higher than people who have been doing this for five years, and these are first-time teaching assistants.

 

Next thing we’ll check on is are their grades getting better and other things you can measure. But so far, the acceptance of the teachers is already better because there’s an attempt to personalize the experience. And so the students are accepting the teachers more, and by the same token, I assume they’re accepting the science more.

 

MSDF

Have you ever thought of designing a curriculum that could be put into the science graduate programs, because these people are going to become scientists?

 

Mr. Alda

What we’ve actually done is introduced a curriculum into Stony Brook University where I helped the Center for Communicating Science. And there are courses for credit taught to graduate students, and in addition there’s even at least one department that requires that the students take these communication courses. So it’s beginning to be seen as an essential element of the science education. And it’s a small beginning. But my feeling has always been isn’t communication essential to science itself, don’t we need to communicate science in order for it to take place or for the benefits of science to come to the surface? And not only that, that’s practical, but for the beauty of science to be enjoyed by the whole world, you definitely need communication. And that will help more science get done, and better science get done. More people entering science, if they understand how beautiful and engrossing it is – exciting. So it seems to me that since communication is such an important part of science, shouldn’t it be taught as part of a science education so that when you graduate as a capable scientist, you’re also a capable communicator?

 

MSDF

Maybe you don’t even have an idea of this answer, but what got you into this passion for science?

 

Mr. Alda

I’ve always been curious and that made me want to know more. I started reading Scientific American in my early 20s and since then I’ve read almost every article in almost every issue. And I love it, I just love it! I mean, I put the magazine down and I read other science magazines – I read Science & Nature and Science News, which I think does a very good job. Just the other day, I just slammed it down on the table and I said to my wife, “Arlene, you won’t believe this, listen to this.” You hear these wonderful stories of things you never imagined.

 

MSDF

No, I agree. I mean, some people get turned off by it, some people get turned on by it.

 

Mr. Alda

Well, it’s hard to believe anybody would get turned off by it unless they’re not hearing it the right way.

 

MSDF

I think that a lot of people are turned off early because they weren’t encouraged or they were led to believe they couldn’t understand it.

 

Mr. Alda

Yeah, it’s true.

 

MSDF

I appreciate it. Thanks.

 

Mr. Alda

Well, thank you very much.

 

[transition music]

 

Thank you for listening to Episode Twenty-Five of Multiple Sclerosis Discovery, our final episode for 2014. We’ll be taking a two-week hiatus for the holidays, but we’ll be back with new weekly episodes starting on January fifth.

 

This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

 [outro music]

 

[intro music]

 

Hello, and welcome to Episode Twenty-four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with Professor Aksel Siva about asymptomatic MS. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

We just uploaded a new data visualization to our website. This one breaks down the design of MRI-related clinical trials in MS. It combines 88 trials conducted between 1998 and 2013 in a colorful, interactive dot plot. Each dot represents a point in time for a particular measurement, such as brain volume. You can sort trials by phase, and you can look at trials in aggregate or one at a time. To view this new visualization, go to the Data Viz section under the “Research Resources” tab and click on the top link.

 

Magnetic resonance imaging is a source of anxiety for many people with MS. Just getting into the machine is nerve-wracking, and waiting for the results is even scarier, says a recent study from PLOS One. The researchers conducting the study suggested that educating patients about MRIs might alleviate some of the dread. Even though MSer’s typically know a great deal about MRIs, understanding how to interpret their own results may help increase the bond of trust with their physicians, the researchers said. To read more about the study, visit our “News and Future Directions” section, and under “News Briefs” click on the article, “MRI Education May Benefit MSers.”

 

Have a burning question? A bone to pick? Something you want to get off your chest? Start a discussion! We invite you to participate in our discussion forums by making your own threads and commenting on others. Just click on the “Discussions” option under the “Forums” tab on our website to get started.

 

[transition music]

 

Now to the interview. Last week, we spoke with Professor Aksel Siva about radiologically isolated syndrome. This week he’ll be speaking to us about asymptomatic MS and approaches to medicine in Turkey.

 

Interviewer – Dan Keller

Professor Siva, first of all, why is it MS if it’s asymptomatic?

 

Interviewee – Aksel Siva

Well, that’s a very good question and very difficult. But now with the tools that we have in medicine, we probably diagnose people without developing the disease. And, again, if we look to some other neurological diseases, today we are now discussing whether we can really diagnose Alzheimer prior that the individual develop the disease with imaging, with biomarkers, and so on. So to see the same thing in MS, I think it’s not really something very different. The thing is that not all these people will develop the disease, so the way we have been trained as clinicians, to us it’s important to see clinical signs and symptoms. 

 

But now we have to start seeing that not everybody will develop the disease even if they do have it biologically, morphologically, or whatever you name it, however you name it. And then when they develop, we know well that all people are not going to have the same course. So these individual differences based on genetic background, maybe environmental influence, or whatever, should put a light in the way we see individuals – not a disease, but the individual with the disease rather let’s to say than the disease affecting the individuals. So I think this concept of subclinical disease, which is not only for MS, should influence our practice or our approach to our patients, and also in understanding the diseases and how to manage them. 

 

MSDF

Can you tell me a little bit about some of the studies that show heightened susceptibility and that possibly invoke the idea of genetics or environment?

 

Professor Siva

I don’t think that I am in a state of responding to this question, because this is not really my area of interest. But from the genetic studies, we know there are some people who have the susceptibility genes, some who have the protective genes, and also some genes that may probably affect the course and prognosis of the patients. But, again, to my knowledge, what we have today, the information we have, is not really unique for everybody. It’s also very heterogeneous. So we need more time, and I think that this time it’s not too far, and especially the Genetic Consortium in the US, their findings are going to bring a lot of new information in the very near future.

 

 

MSDF

What about studies on twins or just siblings. Although it doesn’t really nail down whether it’s genetic or environmental, it does speak to heightened risk. What did those show? Who looked at them and what did they find?

 

Professor Siva

Well, again, I’m not aware of really very new studies on twins; identical and non-identical twins, the risk is very different, it’s maybe 2 to 3% up to 5%, depending like if it’s Canada or France it changes. But when it is identical, it’s 25 to 30. To my knowledge, the Canada cohort went up to 37%, although this number, I guess, was not published, but we know this. So it’s about only one-third even in the highest identical twin studies. So the question is what happens to the two-thirds? Maybe some of them do have incidental lesions, but they don’t have the disease. What is the present state in this genetics or others, I’m not aware of.

 

MSDF

Even siblings who show oligoclonal bands don’t necessarily have or get the disease, is that correct?

 

Professor Siva

No, that’s correct. According to the Swedish study, these people did not have the disease. Maybe more important, there was a subsequent paper reported in the same cohort, they have looked in the CSF of these asymptomatic, or let’s say of these siblings with positive oligoclonal bands, and what they called immunopathic trait. They looked in some other issues, but let’s put it these people with positive oligoclonal bands and the immunopathic trait, and they have looked in some neuronal degeneration markers. And the sibling who had the disease had high levels, which shows that there was a CNS damage, and asymptomatic case it was normal. So that is very clear that, yes, if you get the disease you might have some, let’s say, the biological evidence of it together with CNS damage, whereas if you don’t get… you may have the same trait but not the disease, because you will not have CNS damage. And there might be some underlying mechanisms – immunogenetic, whatever – which controls the disease spread and clinical expression. So I think this is a major issue. 

 

And in the Steffano study when he had studied, again, the relatives of people with MS who had lesions – these 4% or 10% of asymptomatic cases – he also looked in the normal-appearing white matter. And in the diseased individuals it was abnormal; whereas in the people who had just those, let’s say, T2 changes, the normal-appearing white matter was completely normal, which again shows us that the CNS damage is very, very limited in people who don’t get the disease. And from the early autopsy studies, again the people in whom the autopsy had shown brain lesions, they were mostly periventricular and probably in silent areas, and there was not widespread damage as we see in people who get the clinical disease. 

 

MSDF

It seems Turkey is a very good setting for looking at a lot of this, because people get a lot of MRIs.

 

Professor Siva

That’s correct, that’s very correct, and that’s why we have so many cases. Today with contribution of another medical school from Ankara, Hacettepe Medical School, together now we have more than 86 RIS cases that we continue to follow up, some of who have converted now. 

 

MSDF

And RIS is radiological isolated syndrome. Do people pay for their MRIs, or why are they so apt to come in and get so many?

 

Professor Siva

Not really, it’s reimbursed, mostly it’s reimbursed, or if they have their private insurance because, let’s say, physician is suspecting something. And I should also confess that in some hospitals – mainly state hospitals – there is an overload of patients. Let’s say neurologists in those institutions may not find time to listen and examine the patient as they should do. So in order not to miss something, even a patient who comes with a headache may get an MRI.

 

MSDF

Is there a difference in Turkey of how you approach MS patients, or treat them, or follow them from in other countries that you’ve noticed?

 

Professor Siva

Not really. It’s, I would say, very much the same. I have started our MS clinic in 1987 here, and today we have more than 7,000 registered patients, which is really quite a very large population. This doesn’t mean that we follow all the 7,000 and more patients because many of them had been referred for second opinions, but I would say we continue to see at least half of these people. And the way the practice is here is not any different than most major European and US centers. I had spent some time at Mayo many years ago and I had some of my other colleagues now who had spent some time. So it’s more or less the same. We have all the same drugs, most of them are reimbursed. So we have many alternatives for our MS patients, although there are some restrictions for reimbursement. We need to at least try the so-called injectables in order to go to orals, or, let’s say, the monoclonal antibody therapies, but almost all are available. And according to some rules, they are also reimbursed. 

 

MSDF

Are there good patient support services, psychosocial and other?

 

Professor Siva

Not maybe so strong. That we may differ a bit from Europe and US. We do have Turkish MS Society where such services are tried to be provided, but that is not enough. We do have some MS Society chapters in some cities but not everywhere. But mostly the problem, I would say, is economical. All these services mostly are based on voluntary basis.

 

MSDF

Do you think that patients react the same to their disease?

 

Professor Siva

We do have some studies – psychologically, physically – and it’s at very similar to western theories. So actually Turks are Caucasians mostly, and therefore it’s what if we are going to call the western-type MS, that’s what we see here too.

 

MSDF

Are there cultural differences in various parts of Turkey how people view their disease, or is it all about the same? I mean, Istanbul is really Europe, as you move farther east you get into more Asian and Middle Eastern.

 

Professor Siva

I may say not really, because we get referrals from all around Turkey, and the behavior is not really much different. I should say either whether the patient is from Istanbul or from the east part of the country or the Mediterranean, it’s more or less the same.

 

MSDF 

Anything important to add that we’ve missed or interesting topic points?

 

Professor Siva

We have a large number of MS people in Turkey, probably prevalence rate is around 50 per 100,000 or more. There have been a number of prevalence studies, and this is about what we can really derive from all the studies – 50 or more even. But I have the impression that we are getting more and more MS in Turkey today, and more familial cases, which was not the case maybe 15 to 20 years ago.

 

MSDF

Very good. Thanks a lot.

 

Professor Siva

Thank you.

 

[transition music]

 

Thank you for listening to Episode Twenty-four of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations. 

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

 [outro music]

 

[intro music]

 

Hello, and welcome to Episode Twenty-three of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with Professor Aksel Siva about radiologically isolated syndrome. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

The role of diet in MS is a longstanding question, for which there many opinions, but few definitive answers. Researchers and clinicians know little about how diet may contribute to the risk of developing MS, and how it may help or hurt the progress of the disease once it starts. Nevertheless, patients are pushing for answers, hoping that there is more they can do to help slow their disease. We recently published a story looking into all the facts and myths of diet. We also covered what makes diet so difficult to study in a clinical setting, and where the field is going from here.

 

2015 is just around the corner, and deadlines are looming for submitting meeting abstracts and funding applications. Abstract submission deadlines for the Keystone Symposia are coming up in December, and ECTRIMS and the National MS Society have deadlines for funding opportunities early in January. For more details on the deadlines and how to submit your materials, go to the professional resources tab on our website and click on either “meetings and events” or “funding opportunities.”

 

We have also posted several exciting new job opportunities on our website. Go to the “jobs” section under professional resources to view them. And, if you’re looking for a neurologist, a laboratory technician, a post-doc, or any other position—let us know. We’ll help spread the word on our jobs section and in our weekly newsletter, and it won’t cost you a dime to reach a very choice group of MS professionals. Simply go to the “jobs” section and click on the “submit new item” button under the “Job Listings” header.

 

[transition music]

 

Now to the interview. Professor Aksel Siva is a professor of neurology at Istanbul University in Turkey. His work spans areas from clinical neuroimmunology to neuro-epidemiology to research in headaches. 

 

Interviewer – Dan Keller

When we met he discussed radiologically isolated syndrome or RIS and he starts by describing what it is.

 

Interviewee – Aksel Siva

It is by definition an individual who gets an MRI for another reason such as migraine headache or whatever. Then, it turns out that they have MS looking like lesions in their brains. You cannot explain those lesions with any other pathology. They are not related to the patient's cause of referral for an MRI. Their neurological examination is normal, and these people never have experienced any neurological symptom, which might be consistent with past history of MS whatsoever.

 

It is an MRI diagnosis actually. It is not a clinical diagnosis. The question is whether these people do really have subclinical MS or asymptomatic MS and are they going to develop the disease. So the question is what to do when you see these patients. And this has been recently described as radiologically isolated syndrome by Okuda et al. At that time, there were acute CSF and now Darin is in Texas and at that time his mentor Daniel Pelletier is at Yale. So they have introduced this term. There have been, I would say, three pivotal papers by the French group, Christine Lebrun and her colleagues, and from our center together with Mayo Clinic in Rochester. Then this group came together and we have formed the Radiologically Isolated Syndrome Consortium, which has been later on joined by some other centers from Europe and the U.S. 

 

MDSF

So if you don’t know whether these people will go on to MS or where they stand, what do you do about it? How do you follow them and how many of these people do go on to MS?

 

Professor Siva

The Radiologically Isolated Syndrome Consortium, we have conducted a study, which was published earlier this year in PLoS ONE and we have collected 451 cases with this syndrome. When they were followed, about 34% developed a neurological event consistent with either CIS or primary progressive MS. This means that about one-third of these people, who receive a diagnosis of radiologically isolated syndrome, in five years’ time, will develop clinical MS. And 10% of this group will develop primary progressive MS, which is very similar to what we see in two clinical cohorts. When statistically you follow these up to ten years and this is statistical, it turns out that around 55% will develop the disease. So at ten years’ time, still half of these people will not develop clinical MS. What does this mean? It is not clear, but on the other side, it seems that some people, who do have radiologically lesions consistent with multiple sclerosis and may continue to get new ones, still will not the clinical disease. We have known this from some autopsy studies started to be published in the 1960s, 70s, 80s, that there were cases, autopsy cases, where people turned out to have changes in their brains consistent with multiple sclerosis, but they never had the disease in their lifetime. We have to consider this subpopulation in both understanding the disease and when we should consider to start treatment, or whether we should really treat all people with MS or not.

 

MDSF

There has been a feeling that you don't treat the image, but you treat the disease, but a lot of these people do go on to get the disease. Is it time for a randomized trial to see if you treat these people, some of them who would statistically go on, will not go on to get the disease?

 

Professor Siva

It is time to start a treatment trial in RIS and our EOS colleagues, mainly Darin Okuda and Daniel Pelletier and Orhun Kantarci will be starting such a study in the U.S. later this year. There is also another probable trial that might start in Europe by Christine Lebrun. Yes we have come to this era, and probably within let's say a few years, we will have more evidence regarding who should be treated or who should not be when they present with RIS.

 

MDSF

In the study that you looked at people for five years, what did you see were some of the risk factors for going on to MS?

 

Professor Siva

There were some clear-cut risk factors and this was, as already shown by Darin and their group in EOS [?] a couple of years ago, having a spinal cord lesion at the time of the RIS diagnosis is a predictive factor to develop MS. Other factors are male gender and younger age; because when we have looked in this RIS cohort of the 450 or so cases, the mean age of diagnosis was 37, which is older than the general mean age that we diagnose MS. So this should be also taught whether this is because we have just by coincidence we get these incidental lesions in some people who will never develop the disease. 

 

MDSF

Now this study started a while ago to be able to be published recently. In that amount of time people have been looking at a lot of biomarkers. Did you consider biomarkers at that time? Can you find something that is predictive of going on to MS?

 

Professor Siva

Not yet. Actually this study was a retrospective study, but in part it was prospective because in our center we have been interested in this for more than ten years now, almost 15 years. I should say that in Turkey we have a lot of MRIs and the cost is very low. It is very practical for, let's say general neurologists to refer patients for headaches, for not otherwise you would refer for a MRI, to refer them to MRIs, and then suddenly you started to see this MS looking-like lesions. As we have in MS center, we had a lot of referrals and then we started to follow these people. It’s been more or less the same in the other centers. It is yes, a retrospective data collection, but most of this cohort has been prospectively followed in those centers from the time of their admittance. And your question was whether there was a biomarker other than imaging, not really. Not yet, let's put it that way.

 

MDSF

So is it advisable to follow them with imaging and if so, how often?

 

Professor Siva

It is what we are doing now. There have been some suggested algorithms, but what we do in our center, we ask those patients to have a followup MRI in six months. Then within another six months, unless they develop something clinical, and then if they continue to have changes or not in their MRIs, that depends on how frequently we start to follow them up by MRI. Our tendency is twice for the first six months and then yearly for the next two years and then three years or two years later, unless they develop a clinical event consistent with MS or whatever.

 

MDSF

Necessarily these interval MRIs are really snapshots, even in MS lesions come and go. I suppose it would be possible to miss a lesion that was there and that isn't there at the time of the MRI.

 

Professor Siva

Definitely. But it has been shown, again in our study, that about two-thirds of these people continue to have new MRI lesions, but only one-third of the whole population develop a CIS or other event consistent with MS. Having new lesions doesn't really mean that the risk is much higher. Developing new MRI lesions is not always equal to develop the disease or having a much higher risk. It has been shown by the Queen Square Group many years ago when they have followed people who were admitted with CIS for up to 20 years. Ten to 15 % of these populations who presented with CIS, mostly optic neuritis continued to have new lesions, but they never developed a second clinical attack. It is more or less, I believe, for RIS some of those people will continue to have maybe one or two lesions when you do a followup MRI, but that doesn't mean that they necessarily will develop the disease. Even having positive oligoclonal bands is not a much higher risk by itself.

 

MDSF

It would be quite a burden to treat 100% of the RIS population to be able to avert a progression to MS in about a third or over ten years about 55%. I guess, what you really need to do is be able to figure out who will progress. I guess a subpart of that question is, how do you know, or do you know, who will go on to primary progressive MS?

 

Professor Siva

Well we cannot say this when they don't have any clinical symptoms and signs, because in our center we had three such patients who developed primary progressive MS after a period of four to eight years, when we have followed them radiologically. Probably another question is, whether all primary progressive MSs are really primary progressive, or are let's say secondary progressive MS, the diagnosis was done when they have gone through all of the let's say CIS, relapsing-remitting MS subclinically, and when they have entered in the secondary progressive phase, then, the disease became clinically surfaced and because of this we thought that this was people who were primary progressive. Because when you look at these people and we had those…well the whole group, the RIS we have more such cases, which is now prepared for publication. These people continue to have new lesions and they are not really any different than the relapsing-remitting cases. This is another issue that we should consider.

 

MDSF

So in essence asymptomatic MS might really be MS and what looks like primary progressive is really secondary progressive.

 

Professor Silva

Could be. That is a possibility. If I am not wrong, it was the late Charles Poser who had suggested that a number of MS patients the disease goes subclinically for a certain period of time, but they continue to have axonal degeneration and after a certain threshold they become only clinically symptomatic. It might be an analogy between this view and what we have observed.

 

MDSF

Is there anything important to add on the subject of RIS?

 

Professor Silva

Our approach is on an individual basis. Yes, we do have some evidence, we do have some findings, but that doesn't mean that when you see an individual with RIS they will do how it is expected according to the present evidence. When I am with my patients, or I shouldn't call them patients, but the individuals with RIS, my approach is on an individual basis. If they continue to have new MRI lesions and it is really high T2 load on the MRI, we ask for a CNS study, if they have positive oligoclonal bands, they have but normal visual evoked potentials; they have family members and so on. The way I approach those individuals is a little bit different than someone who has a few lesions, just enough to make a diagnosis of RIS, but don't have really other risk factors, no spinal cord and so on. When it comes to the patients we should make our decisions on an individual basis. I do not treat people RIS, but there might be some exceptions.

 

MDSF

Very good, I appreciate it.

 

[transition music]

 

Thank you for listening to Episode Twenty-three of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. 

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

 [outro music]

 

[intro music]

 

Hello, and welcome to Episode Twenty-two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with Dr. Paul Matthews about the Optimize project in the United Kingdom. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

Some good news came from the pharmaceutical company Genzyme. On November 14^th at 9 pm Eastern time, the FDA approved the drug alemtuzumab – trade name Lemtrada – for relapsing forms of MS. The FDA previously rejected the drug in 2013 due to concerns about study design and side effects. There is still some concern over safety, though, so the company is releasing it to only a limited number of patients. The prescription will also come with a host of other drugs to protect against harmful side effects. Researchers aren’t quite sure how the drug works, but it appears to target monocytes, T cells, and B cells.

 

Researchers announced a new mouse model for fatigue at the 2014 Society for Neuroscience meeting in Washington, D.C. The model works by enhancing expression of the pro-inflammatory cytokine, interleukin-1-beta. The model caused mice to reduce physical activity, without showing other signs of illness such as fever or anhedonia. Middle-aged and aged female mice were most affected by the treatment, whereas young mice showed no difference in signs of fatigue. The model gives credence to the idea that fatigue is not produced from dysfunction in the arousal system, but rather is a result of inflammation. The researchers said that they hoped the model will help illuminate the neurobiology of fatigue, the most common and debilitating symptom of MS.

 

If you would like to keep up with all things MSDF, please consider subscribing to our weekly newsletter. We keep our newsletter up-to-date with all of our news stories, blogs, and items from our professional and research resource sections. We’re also on Twitter; follow us at msdforum. And on Facebook, you can like us at facebook.com/ms discovery forum.

 

[transition music]

 

Now to the interview. Professor Paul Matthews is at Imperial College London in brain sciences. Last week he talked with MSDF about imaging in MS. This week we’re discussing his involvement in a UK-based project intended to optimize and personalize MS treatment.

 

Interviewer – Dan Keller

Welcome, Professor Matthews. You’re participating in the Optimize project in the UK. Can you tell me about that?

 

Interviewee – Paul Matthews

Well, thanks, Dan. Optimize has been an exciting journey and we’re still at the early stages, but let me tell you a little bit about it. Over three years ago, a number of us got together to discuss what the barriers to development of stratified or personalized medicine for multiple sclerosis was. We all recognized what the potential could be if we could really figure out how to target medicines to responders, we would have a way of most appropriately staging the introduction of different medicines across patient populations, not exposing people who didn’t need them to drugs of higher risk and insuring that those who did need them got them early. This is a particular problem in the United Kingdom where there is a much more formal process for progressing from first-line DMTs to more powerful agents. And, in fact, there’s also – dare I say it – I mean, a frank therapeutic nihilism and a surprisingly small number of MS patients receive treatment because of the perceived lack of benefit to many of these first-line therapies.

 

Now how to change this. I think what we realized is that we need to have much more granular data on the characteristics of patients being treated and how they fared after their treatment over the long-term. The data provided within the usual clinical context is not only limited, but it ends up being rather patchy over time. In order to enable that, we needed tools that would both collect data and incentivize collection of complete data of high quality. Now a note about this. We all know how to do this within the context of clinical trials, but it’s hugely expensive; it’s expensive because there are multiple people always involved to crosscheck that the data is completely acquired in each paper, and secondarily, there are audit procedures in place in retrospect to insure that this is being done. This really isn’t feasible in routine clinical practice.

 

A colleague of mine, Rory Collins, who has specialized in setting up very large-scale clinical trials in areas like China and India, has shown how very simple electronic tools can help both insure that data is acquired completely and that there is an electronic audit trail to follow-up on data that isn’t. What they showed is that by creating simple electronic questionnaires that wouldn’t let the questionnaire be closed unless data of an appropriate type was entered in the field, and then automatically interrogating the data for quality from center to center and following up where there were potential lapses, one could begin to incentivize acquisition of the right data and actually make it flow faster.

 

So how could we make this happen within the MS space in the UK? Well, what we realized is that the toolkits were all there. The EU IMI program already has funded my colleague, Yike Guo, who’s head of the Imperial College Data Science Institute, to create a tool built around a platform called eTRIKS. This is a data management environment that allows links to apps or iPads or any other peripheral electronic tool for very powerful distributed data capture. We then, in gathering together a number of stakeholder meetings which involved people with MS, the MS societies, a number of industry representatives, and what I’m really pleased to say is leads from fully 18 of the major MS centers across the United Kingdom pretty much ringing the country, together created the vision of building such an electronic tool, distributing the types of input devices across the different centers, and beginning to create a database that could be held centrally or in a distributed fashion using all the new tricks of modern IT.

 

The first thing is acquiring the data, the second is doing useful with it. The second thing that’s rather neat about the eTRIKS platform is that we have shown how it can be built to allow different levels of access, so that there can be access by high-level users who get to see the whole dataset, but also by specialized users who might want to see only a part of it – like a doctor interrogating it for his or her patient – or, importantly, a person with MS interrogating it to see how the data that they have entered stands relative to that that’s entered across the country by all patients; it allows people with MS to begin to gauge how they’re doing relative to others with their disease.

 

Now, I think the latter point is worth building on, because I think all of us have been hugely impressed by the power of sites like Patients Like Me to engage people with the disease in the dialog about their disease and make them full participants in capturing data information. With this kind of distributed data platform where doctors and people with MS can enter data whenever and wherever they are to a central database which can organize it and allow it then to be interrogated as needed, means that we can begin to think about asking patients to enter data on the fly from home. Why is this important? Well, this actually completely transforms the way in which we understand the disease, it really gives us a much deeper sense of the patient experience. Rather than sampling a patient once every month or once every six months, we can actually capture how they’re doing through a day. And if we add to this some extra sensor technologies – say, for example, about movement – we can literally do this from moment to moment.

 

So the vision thus is that if we can use these modern IT tools to capture data from distributed sources – from doctors using iPads, from patients using apps, from sensors that people with MS wear – we can capture data in a central resource that can be distributed to those for the purposes that they need it in near real-time, and in turn provide a common environment for its analysis. I think it’s exciting. Now we’re at the early stages, the basic tools have been designed, we’re starting to build the sensor technology. And our genuine hope is with the completion of the first set of agreements with one of the companies who’s been the first to really take a plunge with us, we’re going to be able to create a beta form of the tool in 6-9 months.

 

Now before closing, I do want to add one thing. This is an exciting vision but the notion of building a database is hardly a new one and many people have had it. There is something that’s special about this vision and it’s the thing that I’m most proud of that’s come together from all of these stakeholders. It’s the vision of creating a database that will be an open database; open to all researchers once it’s built, not held privately by those who built it. And I think this is what could become a game-changer. Moreover, we see that the tools that we’re building in order to create this – the IT tools, the distributed apps, and so on – are tools that the community should own and should be able to improve on. So our intention is fully, as this program develops, to release a software for open-access use as well as the data. Our hope is that even if this doesn’t provide the solution of the future, it will begin to incentivize this kind of practice where we all share this important data to work together to find solutions to this disease.

 

MSDF

Besides collecting MS-specific data, will it also look at general health and comorbidities to see how that affects outcomes?

 

Dr. Matthews

No. That’s a really good question. Like so many doctors now, we’re very much focused on the progressive forms of the disease. Our belief is that comorbidities make major contributions to this, and that by influencing these comorbidities we may have the biggest short-term impact on our patients’ lives. So one of the advantages of a big data capture tool is that we can capture data on all of the other disorders that afflict people with MS, as well, and begin with, again, greater granularity because of contributions from people with as well as their doctors to look at this in ways that wonderful databases like NARCOMS haven’t been able to do. This is an important task for the future and one that we really want to grasp. We’re hoping with further funding to be able to link this to bioresources, as well, and the ability to access a patient’s fluid samples for Omics analyses certainly can add greatly to this.

 

MSDF

Very good, I appreciate it.

 

Dr. Matthews

You’re welcome, Dan, it’s been good speaking to you.

 

[transition music]

 

Thank you for listening to Episode Twenty-two of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

 [outro music]

 

[intro music]

 

Host – Dan Keller

Hello, and welcome to Episode Twenty-one of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with Dr. Paul Matthews about imaging in multiple sclerosis. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

We recently reported on a draft of a review released by the Agency for Healthcare and Research Quality about discontinuing disease-modifying therapies in patients with MS. Though the report’s main conclusion was that little evidence is available to assess the risks and benefits of discontinuing therapies, several MS groups came together to criticize the report during the open comment period. Groups like the National MS Society and Medical Partners 4 MS raised concerns that the review was not conducted properly and that insurance providers may use it as justification to reduce coverage of DMTs for MS. The AHRQ told Multiple Sclerosis Discovery Forum that they would consider the comments carefully and make any necessary revisions.

 

MSDF’s parent organization, the Accelerated Cure Project, is launching a new research resource called iConquer MS. Hollie Schmidt, Vice President of Scientific Operations at the Accelerated Cure Project, recently wrote a blog post explaining that the new initiative aims to take data and biosamples from 20,000 people with MS and make them open-access to researchers. We want your input about what you may want to do with such a resource. If you’re interested, go to the blogs section of MS Discovery Forum under the “News and Future Directions” tab and click on the blog post titled, “Invitation to Share Your Thoughts on a New MS Research Resource.”

 

Our list of meetings and events is ever-growing. We’ve posted multiple meetings of all shapes and sizes sprinkled throughout 2015 and even into 2016. And if you know of a meeting that’s not yet listed, please do submit what information you have. We’ll take care of the rest. Just go to “Meetings and Events” under the “Professional Resources” tab on our website and click on the “submit new item” button to tell us about your event. We’re even willing to list local departmental seminars and journal clubs.

 

[transition music]

 

Now to the interview. Professor Paul Matthews is at Imperial College London in brain sciences. He met with MSDF to talk shop about imaging in MS.

 

Interviewer – Dan Keller

Welcome, Professor Matthews. What do you see now as new modalities or new ways of doing imaging, and what’s coming along?

 

Interviewee - Paul Matthews

Thanks, Dan. Imaging continues to reinvent itself in areas particularly like MS. Magnetic resonance is becoming more and more powerful with use of particularly multiband techniques, allowing multiple coils to be used to accelerate the imaging process, and because of that being able to collect much more data to enhance particularly diffusion images. So, for example, within the Human Connectome Project, development of new multiband techniques has accelerated imaging to the point where very high resolution diffusion tensor images can be acquired in spaces of 15-20 minutes. The implications of this for MS are that we can begin to develop powerful approaches to expression of the diffusion tensor information in terms of diffusion parallel to the fibers, perpendicular to the fibers, and free diffusion that is anisotropic. This means that potentially we’re going to be able to separate out free-water contributions from those contributions arising from myelin and axonal loss, providing a very powerful complement to magnetization transfer images.

 

A second area of major development in magnetic resonance is the increased use of ultra-high field systems at 7T, and potentially higher, for applications in MS. The first advantage this has brought is for increased spatial resolution that can be used to begin to image cortical lesions with a really impressively enhanced sensitivity. The second area has been new kinds of contrast. The high magnetic fields allow new susceptibility-weighted contrast to be generated which provides a powerful way of visualizing vessels. It’s very clearly defining the vessels at the center of most of the inflammatory lesions, helping a little bit with differential diagnosis, but even more importantly helping us understand what the microvascular architecture is in and around lesions.

 

A second potential advantage of the ultra-high field is simply increasing the sensitivity of MR for applications in magnetic resonance spectroscopy. We’ve known for a long time that signals from myo-inositol can help us understand glial components of inflammatory lesions, but there’s increasing interest in applying this kind of tool to measurements of glutathione, to provide indices related to reactive oxygen species generation, and potentially also to measuring excitotoxic neurotransmitters such as glutamate.

 

In a completely different space, positron emission tomography (PET) has begun to play a renewed kind of role in MS. I’ve always been a little bit disappointed that more wasn’t done with it over the last decade or so since pioneering studies that demonstrated that assessments of energy metabolism based on simply the fluorodeoxyglucose signal not only discriminated people with MS from healthy volunteers, but, more importantly, began to show discrimination between different stages of the disease and a relationship to cognitive impairment, with potentially reversible components with treatment. Now, that still is an area of potential work.

 

But more recently focus has shifted particularly to use of ligands that bind to the 18 kilodalton translocator protein which provides a marker of microglial inflammation in the brain. While it’s not entirely specific and with the caveat that we have little understanding of the relationship between the TSPO expression and the microglial phenotype, it clearly is highlighting some very interesting things. First, we found that the TSPO binding by ligands is increased multifocally in brains of people with MS; it’s increased multifocally in the white matter and in the grey matter. Moreover, increases in binding in both regions are related to degrees of disability; patients with higher disability show increased binding particularly in the cortex.

 

There’s emerging evidence, driven first by elegant preclinical studies done by the Finnish group and some human studies yet to be fully reported, that there are also strong treatment effects with powerful amino modulators. So because this provided us a window that is clearly giving us information distinct from that provided by T2 hyperintense lesions on MRI or by gadolinium enhancement on MRI, it promises a powerful adjunct.

 

And, finally, just to kind of round that idea out, it’s clear that it will be the combination of MR and PET that’s powerful rather than PET replacing MR in some way in our diagnostic or monitoring armamentarium for treatment. One manufacturer has already started supplying commercially integrated MRI-PET systems. Another manufacturer is expected to do so very soon, and potentially a third. This may become a platform for brain imaging that is very powerful for disorders like MS that have multifocal manifestations where the registration – the precise registration – between the MRI and the PET becomes important. Moreover, the potential to use dynamic MRI acquisitions where we’re just imaging very, very rapidly throughout the entire PET scanning period to follow the position of the head within the PET scanner may allow a new kind of precision of special resolution in the PET scan that allows MS studies where we rely on this very much to be done with far greater precision than it’s been possible in the past. So with these developments in MR, with the new radioligands in PET, and with this new technology for integrated MRI-PET, I think the brain imaging is off in incredibly new spaces.

 

Now I can’t close the discussion of imaging without at least making a mention of the revolution in applications of optical coherence tomography that have been conducted over the last five years in particular for MS. This is really exciting, too. It’s an inexpensive examination that can be performed very rapidly in any clinic that provides very high-resolution measures of optic nerve fiber layers, of multifocal edematous regions within the nerve fiber layer, all of which can provide measures to stage MS and its associated neurodegeneration, and potentially to usefully monitor it in assessing the progress of patients on treatments. It’s an exciting time for imaging.

 

Interviewer - MSDF

Now just to clarify, this is optical coherence tomography of the retina and its surrounding structures.

 

Interviewee - Dr. Matthews

Yeah, Dan, thanks for clarifying that. Absolutely. So it’s an eye examination, but it’s an adjunct because the retina is just an extension of what we study in the brain.

 

Interviewer - MSDF

Either using metabolic markers or following metabolism with PET or something else, or using other ligands and markers, can you discern or image where remyelination is occurring?

 

Interviewee - Dr. Matthews

So, of course, the world of PET is a big one because what we can observe changes with the type of radiotracer that we use. Recently, Yanming Wang, who I had the privilege of collaborating with at Case Western, published, I think, a really groundbreaking paper. Although it was a preclinical study, I think it shows the way we could be moving in this space. Using a novel radiotracer that he developed called MeDAS – MeDAS for short – this carbon positron-emitting isotope-incorporated tracer allows specific myelin proteins to be imaged, and thus provides a marker of myelin integrity in life. Yanming has shown how it can selectively image myelin, it can image both established myelin and new myelin being formed, and he demonstrated in a proof of concept study in rodents that the dynamics of demyelination and remyelination following therapeutic intervention can be followed, and moreover, that the therapeutic effect can be quantified relative to an untreated control group.

 

Really exciting and a potentially important adjunct to MTR or diffusion measurements in human studies. The trick of moving a tracer from preclinical studies into humans is not without some need for care, but because only microdoses of these tracers are used for the human imaging experiment, Yanming, myself, and colleagues believe we can make this transition rapidly. We’re watching closely to see what happens next.

 

Interviewer - MSDF

Pretty good. I appreciate it.

 

Interviewee - Dr. Matthews

Thanks, Dan.

 

[transition music]

 

Thank you for listening to Episode Twenty-one of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

 [outro music]

[intro music]

 

Hello, and welcome to Episode Twenty of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with Dr. Jeffery Cohen about two clinical trials. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org. Genome-wide association studies are raising more questions than they answer for multiple sclerosis, according to new research. As the number of risky genetic variants grew, researchers began to wonder if many of those variants would be found in the murky waters of “noncoding DNA,” which comprises about 98% of the human genome. Those fears were confirmed in a study published last month in the journal Nature. According to the report, almost 90% of the risk variants fell within the noncoding region and 60% were found in areas known as enhancers or switches. These areas manage gene activity, though researchers are far from fully understanding how they work. While genome-wide association studies have been helpful to researchers, this study highlights that they are just a first step towards a better understanding of MS and the human genome.

 

The International Progressive MS Alliance recently released a call for applications for their second round of grants. To go along with this announcement, Professor Alan Thompson, the head of the Alliance’s scientific steering committee, penned a post for our blog. In his post, he emphasizes the urgent need for more research into progressive MS. He notes that over one million people worldwide live with progressive MS, yet no specific treatments exist for this condition. You can read Professor Thompson’s post in the blog section of the News and Future directions tab at msdiscovery.org. To get more information about the grants from the Alliance, visit our “Funding Opportunities” section under the “Professional Resources” tab on our website.

 

In addition to the latest funding opportunity from the Progressive MS Alliance, we also recently posted a long list of funding opportunities from the National MS Society.

 

[transition music]

 

Now to the interview. Dr. Jeffrey Cohen is a neurologist and director of the Mellen Center for multiple sclerosis at the Cleveland Clinic. He spoke with MSDF about two clinical trials, one examining the clinical use of stem cells, the other about a generic version of glatiramer acetate, Copaxone.

 

Interviewer – Dan Keller

First of all, what was the aim of the clinical stem cell trial and what phase was it done in?

 

Interviewee – Jeffrey Cohen

So we now have 11 medications approved to treat multiple sclerosis. They are all effective in the early, relapsing remitting stage of the disease, but there is a major unmet need for treatments that repair damage and might be effective in progressive MS. Our main goal was to explore cell-based therapies to treat multiple sclerosis, specifically to test the feasibility and safety of administering so-called mesenchymal stem cells. This was a Phase I study of mesenchymal stem cells. These are stem cells that are present in many tissues of the body. We isolated them from bone marrow which is probably the version that is the best studied previously. We grew them in the laboratory to increase their numbers, and then readministered them intravenously. We were focusing primarily on safety, as I said. We had fairly intense monitoring for any complications. Thankfully, we saw none. We also looked in a very preliminary way for benefit using clinical measures, a variety of imaging approaches and immunologic measures.

 

MSDF

What is the hypothesis here that they are doing? Do they actually get into the brain? You are infusing them IV. There is a blood-brain barrier, these are pretty big objects.

 

Dr. Cohen

There are actually a large number of studies in the laboratory and in animals that suggest that these cells have a number of properties that we think would be of use in a disease like multiple sclerosis. First of all, they seem to modulate the immune response. They dampen down inflammation. But more importantly, they appear to be able to produce a wide range of soluble factors, growth factors and other substances that we think promote repair. We think of them as the delivery system for growth factors that promote repair. We don't think that they themselves develop into brain tissue but will become neuro-cells, but rather that they create a milieu that is conducive for the natural intrinsic repair processes to remyelinate or restore neurologic function. The other property that is potentially very advantageous is that they appear to be attracted to areas of tissue damage or inflammation. They appear to have the ability to migrate within tissues, and in fact to migrate from either the cerebral spinal fluid into the brain or from the blood into the nervous system. So we think we can take advantage of that by administering them intravenously.

 

MSDF

Did you do dose-ranging here?

 

Dr. Cohen: We did not. One of the things we learned from this study is that there are a lot of unknowns about cell-based therapies. What the appropriate dose is? Whether multiple doses are needed? What is the best route of administration? Whether there are nuances as to how you grow the cells in culture? What characteristics you want to augment? Dose-ranging in particular is something that has been very difficult to do in the field, particularly for some of these cells that are grown in culture; you usually have the dose that you have. That has been an issue that we have struggled with as have others in the field.

 

MSDF

How long did you follow these patients and what did you find?

 

Dr. Cohen

We followed them for two months prior to infusion. That is the time during which their cells were being cultured, and then for six months after infusion. So very reassuringly there were no serious or severe adverse events. In fact, there were very little, if any, side effects. Patients were not immunosuppressed. They had no premedication. The only side effect was that the culture media contains a chemical called DSMO. Some patients got a garlic taste in their mouth. If they don't like Italian food, they didn't like that. We also looked in a preliminary way for evidence of benefit with the caveat that this study was not really designed to look for benefit. We used this as an opportunity to explore a variety of measures that might show tissue repair. We saw enticing improvement in some measures in some patients, but for patients as a group, there was no clear-cut evidence of benefit. We have to be very careful how we interpret these results.

 

MSDF

Could you follow them in any way? Were they tagged or any other way that you know where they went?

 

Dr. Cohen

No. That is another aspect of the cell therapy field that is getting a lot of attention. At the moment it is largely a black box. After we administer the cells, knowing whether they survive and where they go and how long they live there. That is another line of research besides pursuing further clinical trials of these cells is also to develop methods to track them within the body. There are some promising approaches that we are in the process of developing.

 

MSDF

Now I take it these were not modified in any way, they were just cultured to multiply them?

 

Dr. Cohen

There were some growth factors in the culture media, but they were from the regulatory point of view, not very manipulated. That is the terminology that is used. That is another area of debate is some of the specifics of the culture approach, whether we should add other factors that might change the properties of the cells. Whether it is okay for them to be frozen, which we do largely for convenience because then we can schedule the infusion. Or whether they should be taken fresh from the culture and administered. There are arguments for both approaches.

 

MSDF

Many cells seem to hone right back to where they came from. Do these just go back to the bone marrow do you think, or do you think they actually went somewhere because that area needed repair?

 

Dr. Cohen

There have been a few studies in some other conditions where these cells have been given. One of the interesting properties is that you can administer these cells from another person and they are not rejected. They become, I wouldn't say the standard, but a very common treatment for what is called graft-versus-host disease, which is a very severe complication of allogeneic bone marrow transplant where the transplanted immune system attacks the recipient's body. That is where the immunomodulatory effects of mesenchymal stem cells were first observed. There are, unfortunately, have been a couple of instances where MSCs that were from another person of a different gender, were administered to someone with graft-versus-host disease who unfortunately, subsequently died of GVH. In those cases, these cells were found in a range of tissues including bone marrow. Probably a more important obstacle is for after intravenous administration is the lung because that is where the blood goes from the veins. These cells probably collect in the lung initially and then percolate out into the tissues.

 

MSDF

Do you have any concerns, any caveats about potential harms, limitations, from using this? Is it feasible on a large scale?

 

Dr. Cohen

We took a very conservative approach with the idea that there are so many unknowns of cell-based therapies, including precedence in multiple sclerosis where therapies had a different effect than we anticipated. We thought it was appropriate to take a very careful systematic approach starting with a small safety study and then building from there. At least within the limitations of our study, meaning that it was relatively short, and relatively small, we saw no indications of any complications. Some of the hypothetical concerns would be cancer. Stem cells share some properties that are similar to cancer cells, or ectopic tissue formation. Stem cells have the natural ability to develop into almost any kind of tissue. At least, presumably they could go to one tissue and develop into another type of cell, so bone within the heart or something like that. We really saw no indication of that. There are really no examples of that in the literature, but because of those sorts of concerns, we took a very careful approach. We feel comfortable now moving on to a bigger program. 

 

MSDF

You had discussed some of the problems that arose using allogeneic cells. Just to clarify, this was using autologous cells?

 

Dr. Cohen

Correct. These were cells from the patient themselves. There is still some debate in the field, which approach is better. Whether to take cells from the person themselves or whether to take cells from someone who does not have the disease that you are treating. That again is an issue that has not been settled. I think some of the cell tracking we were talking about earlier may help with that. Rather than answering all of these questions one trial at a time, we may be able to adjudicate some of these questions by seeing whether cells traffic more effectively.

 

MSDF

Let’s shift to your other trial, the GATE trial using generic Copaxone. Is that available now and what was the point of the trial?

 

Dr. Cohen

The purpose of this trial was potentially to have a generic version of one of the established multiple sclerosis drugs come available. The incentive would be that presumably because of the lower development costs, that the generic version would save money for payers and for patients. The trial we just completed was of a generic version of glatiramer acetate, Copaxone, one of the initial drugs approved to treat MS, a drug that we have a great deal of experience with. It has established efficacy and a known good safety profile. This study tested a generic version of that with the intent of showing that it had equivalent efficacy, in this case, as tested by MRI and had equivalent safety and tolerability.

 

MSDF

These were all patients with relapsing, remitting MS? You had, what, about 735?

 

Dr. Cohen

Correct. This was in a patient population with relapsing, remitting MS; the population for which Copaxone is approved.

 

MSDF

What were the interventions, the test group?

 

Dr. Cohen

There were three groups in this trial. One group was treated with generic glatiramer acetate. One group was treated with the brand Copaxone and then there was also a small placebo group to demonstrate what is called study assay sensitivity. The purpose of which was to show for the trial overall that the generic glatiramer acetate is equivalent to the brand-name, the reference drug as it is called, but also that within this trial with this population, that both drugs were effective.

 

MSDF

Where was this done, and is that ethical?

 

Dr. Cohen

One of the things we have encountered increasingly in developing multiple sclerosis drugs is that there are ethical and practical issues to including placebo groups. At this point it has become extremely difficult to include a placebo group in a large Phase III study that goes on for several years. In this case, this was a short trial, with the advantage of using MRI as the endpoint. It was conducted to some extent in North America, but primarily in Eastern Europe and other  countries where unfortunately, multiple sclerosis treatments are not as available. 

 

MSDF

What did you find?

 

Dr. Cohen

The study was successful. It showed equivalent efficacy as measured by gadolinium-enhanced MRI, and also showed equivalent safety and tolerability as measured by adverse events and injection site tolerability.

 

MSDF

What would this mean for patients if someone brought out a generic?

 

Dr. Cohen

The hope would be, is that if this drug is approved, that it would be less expensive. Multiple sclerosis is an expensive disease to care for and a great part of that cost is medication costs. So the hope would be that this would be less expensive. The other caveat is that complicated molecules such as Copaxone are difficult to replicate. In addition to very extensive chemical and biophysical analyses, that is why a trial was conducted, because of the feeling that it would only be with clinical data that we could…we assure ourselves that this was in fact similar to Copaxone.

 

MSDF

I would take it, that this would only apply to the generic you tested. I mean generics have a certain tolerance level margin compared to the approved brand, so not all generics are the same.

 

Dr. Cohen

That is correct. It is actually quite tricky to develop a generic of a complicated molecule, either a complex mixture such as glatiramer acetate or a so-called biological like a monoclonal antibody. Each one has to be tested one at a time.

 

MSDF

Anything important that we have missed, or to add?

 

Dr. Cohen

This trial was designed with the assistance of, and discussions with EMA, the European Regulatory Agency. It has been somewhat more difficult in the United States. The FDA is still somewhat unclear on their policies and the procedures for testing complex generics and biosimilars. The status of this trial in the United States is still somewhat uncertain.

 

MSDF

Very good. Thank you.

 

Dr. Cohen

Thank you.

 

[transition music]

 

Thank you for listening to Episode Twenty of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations. 

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

[outro music]

 

 

[intro music]

 

Host – Dan Keller

Hello, and welcome to Episode Nineteen of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features the second half of an interview with Dr. Samuel Ludwin. This time Dr. Ludwin and I discuss the implications of treating multiple sclerosis subtypes. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

This week we reported some good news: a large case-controlled study showed that there is no causal link between vaccines and multiple sclerosis. However, the study came with the caveat that there is some increased risk for developing MS in younger patients who receive vaccines. This increased risk is likely due to the vaccines triggering a pre-existing asymptomatic condition, the researchers said. The study, which was published in the journal JAMA Neurology, was most concerned with the role that vaccines for hepatitis B and human papillomavirus play in the long-term risk for developing MS.

 

We also reported on a new iPad app that will allow clinicians and MS patients to track their disease course. The app, called Bioscreen, is currently in beta-testing at the University of California, San Francisco. The developers, including Pierre-Antoine Gourraud who is on MSDF’s scientific advisory board, assert that Bioscreen has the potential to be a powerful tool for researchers, clinicians, and patients. At the core of the app is a dataset of around 600 patients who have been participating in a data collection survey for the past 10 years. Physicians can compare their patient’s disease course with other confirmed MS cases and use that information to influence their recommendations. The researchers also believe that patients’ ability to visualize their own disease in this way will improve adherence to medical recommendations and ultimately strengthen the bond between patient and physician.

 

Every week we publish at least one “Research Roundup” where we curate stories from around the web related to multiple sclerosis. Recently we published roundups about advances in spinal cord injury treatment, the recipe for selling the perfect bogus drug, and the report of a rare brain infection in a patient taking dimethyl fumarate, trade name Tecfidera. To view Research Roundups, go to the “News Briefs” section of the “News and Future Directions” tab at msdiscovery.org. Look for the blue Research Roundup logo and stay up-to-date with all the latest MS news.

 

[transition music]

 

Now to the interview with Dr. Samuel Ludwin, a neuropathologist who is currently a visiting scientist at the Montreal Neurological Institute. Last week we aired an interview with Dr. Ludwin in which he discussed remyelination therapies. This week he speaks with MSDF about MS subtypes.

 

Interviewer – Dan Keller

Welcome, Dr. Ludwin. Let’s talk about some of the subgroups of multiple sclerosis, as has been proposed by Professor Hans Lassmann, and you wrote an editorial some time ago about it. First of all, can you tell me what subgroups he identified and what progress there has been made since then?

 

Interviewee – Samuel Ludwin

This is a very groundbreaking paper, very controversial, and over the years many people who have followed this particular pattern, others who’ve not been able to reproduce it and believe that the conclusions are not valid. However, what Claudia Lucchinetti and Hans Lassmann showed in a mammoth first-time examination of very acute lesions; they had access to a particularly unique group of specimens that are from both the Mayo Clinic and other areas, where very early lesions were examined. And in looking at this, they looked at patterns of tissue breakdown and the mechanisms of tissue breakdown, and essentially came up with four different categories. The two most important ones are very important to discuss because in the one, the features were very, very consistent with the kind of immune injury that one finds in experimental allergic encephalomyelitis where we know the damage has been caused by the injection of the antigen with a subsequent immune reaction to that antigen. And the other main group was one where there appeared to be a primary damage of some sort to the oligodendrocyte and then a subsequent immune reaction.

 

Now this is important for a couple of reasons, and the first is that there is a big debate going on in the multiple sclerosis literature or research as to whether the disease starts from the outside peripheral activation of immune cells and then homes in on the brain because they are cross-antigens or cross-antibodies or cross-cells, or whether the process actually starts with damage to something in the brain which subsequently sets off the – and this is called the “inside-out” or “outside-in” controversy at the same time. What this might mean, according to the way they have done the study – which was a very good one – was they suggested that there might be multiple mechanisms towards the end result of damage to oligodendrocytes and myelin, and subsequently the physical appearance of multiple sclerosis lesions.

 

Other people have challenged this and suggested that maybe it is a question of timing, and the mechanism is the same in all patients, but we’re looking at a different kind of progression and timing. And that controversy is still being discussed, as is the inside-out, outside-in phenomenon. But when you look at some of the things that might be causing these inside-out or their type 3 pattern where the primary damage could be in the oligodendrocyte, there are many reasons that the mechanism could be due to either stroke-like causes such as a lack of oxygen or blood flow that damages the oligodendrocyte, possibly certain infections that may target the oligodendrocyte. And we know that there are many mouse models where you can target oligodendrocytes with certain viruses. And those overlap very significantly with mechanisms of tissue damage in other diseases.

 

So it is a very important paper because it has set people thinking about multiple mechanisms. The fallout from this is that, in fact, when you have different mechanisms of causing disease, there are potentially different ways of treating it. And if you have a primary immune-based phenomenon from the outside, antiinflammatories as are given on disease-modifying therapies are perhaps the way to go, whereas if you’ve got something that is damaging it from the inside and some other cause, we need to elucidate what that cause is and go straight for that particular cause. In addition, what we are trying to find out is whether we can predict what sort of pattern has caused the disease, either with imaging or with biomarkers, and be able to do this without biopsies and other things so that patients can be treated accordingly. It’s an advance on perhaps what we might call personalized medicine in multiple sclerosis. 

 

MSDF

Are there imaging or clinical correlates of these different types of processes? You’re not going to do a biopsy on most people.

 

Dr. Ludwin

No, there isn’t. But in fact, there are some therapeutic differences. For instance, in the type 2 pattern, which is the autoimmune pattern or the outside-in pattern, these patients respond very well to plasmapheresis where one is removing the offending gammaglobulin. And patients with the type 3, which is the main oligodendrocyte-based pattern of the disease, they don’t respond to that well. And that’s perhaps the best clinical differentiation that we know at the moment that helps us. A lot of the data is not clear. They based a lot of the data on the fact that they felt that every patient had a uniform pattern in the lesions. Other people have questioned this and found that there might be a multitude of different kind of patterns in the same patient, and therefore it supported modifications of the same inherent cause.

 

MSDF

Does the efficacy of plasmapheresis correlate with the presence of oligoclonal bands in the CSF, or that’s not a correlation?

 

Dr. Ludwin

There doesn’t seem to be a correlation, leastwise I know. Certainly plasmapheresis where we know that there is antibody, such as in neuromyelitis optica is more effective as a treatment early for diseases where we know that there is circulating antibody, but patients will have oligoclonal banding, I think, in both patterns.

 

MSDF

You’d alluded to damage to the oligodendrocyte in one of these forms as the primary dysfunction or lesion. Does that imply that something is being exposed, an antigen that might be reacted to, or how is that leading to damage?

 

Dr. Ludwin

Absolutely, that if you get damage to a tissue, various proteins are being broken down and antigenic epitopes are being exposed, which then are transported back to the peripheral lymphoid tissue for reactions to take place. I mean, there are counter-arguments to this. One can ask why, with a lot of trauma injury, a lot of stroke injury which is far more common than MS, why you don’t get a secondary immune response to that, even though we know many people with the genetic makeup makes them susceptible to MS or exist in the normal population, and almost certainly some of them have strokes. So there are questions on both sides and arguments. And we know from other experiments that you can induce circulating antigens with tissue destruction of any cause, and potentially these are circulating to be able to produce reactive antibodies in the periphery.

 

MSDF

I think Lassmann showed that even in healthy people you can find CNS antigens in the cervical draining lymph nodes, which raises the same question you just brought up; why do some people have a reaction and some not?

 

Dr. Ludwin

Absolutely, and there are now all sorts of theories coming out of the genetics that there are multiple genes, each having a small effect, but in totality may be adding up to a genetic defect that will allow some of these circulating cells to suddenly start having an effect.

 

MSDF

Now it seems, in terms of thinking of personalized medicine, so much of it is empiric – what works works, and you try something else if it doesn’t. Is there a possibility of any harm from these treatments to people for whom it doesn’t work? Do you have to be very concerned about also first not do harm, especially considering you can’t tell the difference among these types from the start?

 

Dr. Ludwin

Yeah, I think that it’s too early to apply personalized medicine to patients in this particular area in the different types. If you’re looking at personalized medicine that, you know, we treat patients as individuals, or we should, because a lot of the therapy is based on empiric choice and anecdotal experience sometimes with the clinician, and there’s no absolute algorithm that everybody uses to treat a patient. So in that sense, we already do practice it. But you’re quite right, a lot of that is anecdotal or empirical rather than mechanistic.

 

The do no harm is a very interesting point also, because you mustn’t forget that basically multiple sclerosis is an inflammatory disease, and very frequently we tend to look at inflammation as being something that’s bad. But the reason the body mounts an inflammatory infiltrate is usually to cure something or to clean up something that is attacking it from the outside. So in any kind of these interferences, we have to choose a very find balance between stopping an inflammatory infiltrate or reaction that may be doing a lot of good for the patient, while preventing it from its worst excesses.

 

And here, empiricism comes in quite well at the moment; we know which of these drugs that we give are more likely to give side effects, we know more about side effects than we do about potential for not allowing growth. We will stop a particular cytokine or block a particular protein in its action, but I think we should always be aware that the protein, if it’s a normal one and not abnormal protein, may be there for a reason and the patients will do worse if they don’t have this mess cleaned up, so to speak.

 

MSDF

We’re also finding today that we’re almost living in a proinflammatory environment; it has repercussions in heart disease, dental disease, MS, fat is proinflammatory. So do all these things add to the risk in MS if there’s other inflammatory processes going on?

 

Dr. Ludwin

Well, it’s not only the inflammatory processes that’s going on, it’s the things that are causing them. As you’re right, we are now discovering that things like salt, fast foods, the changes in the microbiota all tend to make us more proinflammatory. And certainly in experimental animals and now some human studies, it has been shown that experimental immune disease is worsened by a high salt intake which leads to increased salt in the tissues, as well as being prevented by some of these diseases. If you change the gut microbiota in many of these diseases from normal commensals into something that may be pathogenic, you will set off inflammatory autoimmune disease. It’s been shown very beautifully in ulcerative colitis and Crohn’s disease, and the same thing is now being looked at very strongly in multiple sclerosis, so certainly a proinflammatory environment.

 

On the other hand, it should be remembered that there’s certain kind of infections that produce a reaction that may very well be protective, and there’s some evidence that some of the parasites produce a factor and we believe it could be related to a particular type of protective T-cell that will then allow for patients to become resistant to multiple sclerosis. And there’s some very good data from South America that populations who’ve been exposed to parasites and have them are actually more resistant to multiple sclerosis, because the parasite has induced a protective antiinflammatory molecule in the cell as well. So it’s a very complex balance and we’re gradually discovering more and more about where this balance lies.

 

MSDF

Might the prevalence of parasites account, at least in part, for the geographic distribution of MS?

 

Dr. Ludwin

Well, parasites are just one part of it. There is a very strong feeling, and it comes back to also the gut microbiota – but it’s more than just gut microbiota; it’s environment microbiota – that this has a major role. And for many years, it wasn’t just parasites. People in the Third World had a much lower incidence of multiple sclerosis, and this could have been also from genetic reasons or from susceptibility. But it was not just for multiple sclerosis. All autoimmune disease was much lower in frequency in these populations, and the theory was that most of the people who grew up in developing countries were exposed to large numbers of bacteria and they developed robust immune systems, normal-functioning immune systems that could help them deal with it. And the theory is that in developed countries, the over-usage of antibiotics has aborted normal immune responses, and so in response to that autoantibodies are created and we are suffering the consequence of living too clean a life. And so I think if you look at that argument, it’s not just multiple sclerosis, it really has been mooted for the inflammatory bowel disease, juvenile diabetes, rheumatoid arthritis, and other immune diseases as well.

 

MSDF

Thank you, this has been very good.

 

Dr. Ludwin

Pleasure.

 

[transition music]

 

Thank you for listening to Episode Nineteen of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

[outro music]

[intro music]

 

Hello, and welcome to Episode Eighteen of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with Dr. Samuel Ludwin about new approaches to remyelinating therapies. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

The term “neuroscience” makes it very clear who is the star of the show—neurons. But over the past few years, glial cells have been elbowing their way in from supporting cast to stars in their own right. We recently reported a story about how oligodendrocytes need to make new myelin in order for mice to learn a new motor task effectively. The study demonstrated how glia are required in active learning, as well as highlighted the importance of targeting remyelination in new therapies for demyelinating disorders.

 

Speaking of remyelination, we recently published an article in our animal model section about zebrafish and their use in studying MS. Though a fish might not jump to mind as an adequate model for modeling the complexities of a disease like MS, zebrafish are actually very useful for studying myelination. Researchers can engineer the fish to be transparent while also fluorescently tagging myelin, oligodendrocytes, and more. If you’re curious to learn more, go to the “Animal Models” section under “Research Resources” and click on “Zebrafish.”

 

Finally, we recently added a new data visualization examining the differences in baseline characteristics of patients in 74 RRMS and CIS clinical trials. You can easily see how individual trials compare to the overall mean values of gender, age, Expanded Disability Status Scale score, the number of gadolinium enhancing lesions, and the volume of T2 lesions. To see the new data visualization, click on the “Data Visualizations” tab under “Research Resources,” and then click on “RRMS and CIS baseline characteristics.”

 

[transition music]

 

Now to the interview. Dr. Samuel Ludwin is a neuropathologist who is currently a visiting scientist at the Montreal Neurological Institute. He met with MSDF to talk about the latest in remyelination therapies.

 

Interviewer—Dan Keller

In terms of remyelination, what do we know now? Are there new thoughts about mechanisms and are there any compounds in development that would facilitate it?

 

Interviewee—Samuel Ludwin

Remyelination is a very interesting process. We know that it occurs in animals. We can well demonstrate its temporal progression. We can demonstrate the conditions under which it occurs. Demonstrating this in the human is very much more complicated because we are always taking snapshots in time in looking at human specimens and we can never be sure whether we are looking at a remyelination of a previously completely demyelinated process or not. So we draw all of our analogies about human remyelination, which we believe is present in multiple sclerosis and other diseases, but we draw these analogies from what we have shown in experimental animals where we have been able to control the process.

 

In animals, first of all, it is very feasible for a variety of reasons. The first is that – many mammalian, especially rodent brains, and marmoset brains which we generally work on – are considered in a way functionally immature which tends to suggest that their brains are much more capable of plasticity and therefore much more able to be repaired. The same process probably does occur in humans but as I said is probably a little bit less certain. We have done a lot of work in multiple sclerosis in demonstrating that the hallmark of remyelination which is a reconstituted sheath, although with different physical characteristics to the original myelin. We can find these sheaths in the human tissue in areas that we think are remyelinating. This brings up the promise that a certain amount of natural remyelination occurs in response to demyelination in disease. There is always the hope that one can use some of the same factors that we have discovered in rodents and other experimental animals to enhance this remyelination and make for a much wider area of functional…both enhancement of function and also protection of the underlying axons.

 

So remyelination is one of the hopes and maybe promises in multiple sclerosis research. Proving it is a little bit more difficult. We have many possible mechanisms for enhancing remyelination. Some of them are considered to be cell-based. By that we mean what is preventing remyelination often is the destruction of the oligodendrocyte and its precursor cells which can develop into myelinating oligodendrocyte. A lack of these cells will obviously result in a deficient remyelination. Secondly, there may be blocks from either the axon which gives the message and the signal for remyelination. Thirdly, there may be physical barriers such as the reaction from other cells in response to the inflammatory insult that are hindering access by these oligodendrocytes to the axon in order to make myelin.

 

There are many possible reasons that we don't have adequate remyelination. For each of these, there are at least some punitive answers as to how we may enhance. There is a lot of interest in cell transplantation, especially with mesenchymal stem cells at the moment; which have been shown not only to have immunological benefits of antiinflammatory qualities but also to be able to then differentiate into these oligodendrocyte precursors which will then differentiate into myelinating oligodendrocytes. These may enable the brain to reconstitute its quotient of myelinating cells.

 

There are lots of attempts underway to try and prevent any of the physical barriers of access of these cells to the axon such as from the astrocytic gliosis, but there are also many drugs which have the possibility of enhancing human remyelination. Many of these have been shown to work very well in animal models. We have whole classes of drugs that enhance remyelination. There are steroidal compounds that have been shown to enhance myelination and there have been many that have been shown to either block some of the cytokines that may be hindering or interfering with the progression of oligodendrocyte maturation. Drugs that will block some of these cytokines will allow this maturation of proliferation of these cells to continue, and therefore lead to maturation. It is true to say that apart from some of the mesenchymal stem cells which have some hope; it has been very difficult to measure remyelination in response to these therapeutic attempts at the moment in humans. Certainly in rodents we have been able to do it and there are certain clinical trials going on based on some of these animal experiments. There is a trial which the NIH is doing in conjunction with the Myelin Repair Foundation over a compound 008 which has been shown to be very beneficial in certain demyelinating models and enhancing remyelination. There are certain growth factors that have been given in animals such as hepatic growth factor that have been shown to enhance the number of oligodendrocyte precursors and their development into oligodendrocytes. These all give promise for what is possible in humans but have not yet been taken to that level yet.

 

MSDF

It is interesting that some of the drugs are either approved for other uses or they are older drugs or derivatives of older drugs that are now resurfacing in this arena. How do some of those work?

 

Dr. Ludwin

What is very interesting is that there is a whole gamut of drugs that are being investigated ab intio arising out of experiments that have been shown to have an influence on the inflammatory aspect of autoimmune disease. Many of the cytokines induced by the autoimmune diseases have multiple effects on the oligodendrocyte proliferation, maturation and then access to the axon. So drugs that will inhibit this cascade of cytokines in autoimmunity will also remove some of these inhibitors and allow for enhanced proliferation and maturation and therefore enhanced remyelination. In addition, there are a whole emerging group of drugs that have been found to coincidentally have an affect experimentally on remyelination and many of these drugs have been in the pharmacopeia for other diseases and these are side effects or side discoveries. Some of them have not been used for their initial purpose for a long time and this includes a drug that is currently under clinical trials with the NIH and the Myelin Repair Foundation called MRF-008, the details of which are not public, either in mechanism or in the structure of the drug. There are also classes of drugs such as estrogen and progesterone based drugs which have been introduced because of observable influences of normal estrogen progesterone function on oligodendrocytes and Schwann cells in the periphery in culture and they relate also to hormonal variations in multiple sclerosis and are a natural outcome of some of these observations.

 

MSDF

It sounds like those have sort of general repair functions. I mean they are using estrogen or testing it in traumatic brain injury and things like that.

 

Dr. Ludwin

Oh absolutely. I mean when we look at general repair foundations, we are looking at two of them. First of all, there is the whole question of neuroprotection and second of all there is the whole question of regrowth and these in form, are we looking at regrowth of axons, sprouting of axons in multiple sclerosis. There is a large amount of axonal damage which needs to be investigated for protection and such strategies will be very useful in axonal damage and in the hope of producing axonal regeneration.

 

MSDF

Now I guess there is a difference between neuroprotection and remyelination. Some of these drugs do both or do they fall into separate categories?

 

Dr. Ludwin

Some of them may do both but in general the neuroprotective drugs are generally a different class or different kind of drugs. There is a great need to introduce them into stroke, into trauma, the neuroprotective drugs and people are looking at the same strategies that are being used for ischemia and anoxia which are the results of strokes but may also very possibly play a role in the lesions in multiple sclerosis to protect the axons. Some of these are excitotoxic protection agents which the axon is particularly susceptible to both in ischemia and in multiple sclerosis.

 

MSDF

You hear much more in terms of reperfusion injury, the role of excitotoxicity, particularly glutamate. Does that also enter here or is this such a chronic process that you really don't have an accumulation of glutamate?

 

Dr. Ludwin

No, that is a very good question. In fact, neurotransmitter excitotoxicity has been demonstrated very well in multiple sclerosis, especially in the acute lesions where perhaps most of the axonal injury takes place. We always used to think that it was all a progressive lesion but a huge amount takes place early on in and much of this is in excitotoxic damage. I might add also that in many respects the oligodendrocyte has got many of the same neurotransmitter capacities as does the axon and neuron and the oligodendrocyte itself is susceptible to excitotoxic damage as well. Excitotoxicity is a very important target for neuroprotection and protection of the oligodendrocyte as well.

 

MSDF

On these topics, either compounds that look promising or the process of repair itself, what have we missed, or is there anything important to add?

 

Dr. Ludwin

I think that covers it in general. Of course, what we really are looking for is what the triggers to the acute process are. What we are doing, the autoimmune aspect, is the largest looming figure in the one that is proven most and almost certainly represents the major way that tissue is damaged. But what provokes the autoimmune attack may give us the answer to at least preventing or slowing down the AMS process. The therapy is at the moment largely based around dampening of the autoimmune attack and preventing subsequent damage. Although I should point out that it is not only the loss of myelin that leads to excitotoxic damage in the axon but the inflammatory infiltrate that kills oligodendrocytes and myelin has the same mechanisms that kill the axon as well. We are not just trying to protect, we are trying to prevent the axon from being damaged in the first place, early.

 

MSDF

Very good, I appreciate it.

 

[transition music]

 

Thank you for listening to Episode Eighteen of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

 [outro music]

 

 

[intro music]

 

Host – Dan Keller 

Hello, and welcome to Episode Seventeen of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with Dr. Hans Lassmann about the usefulness of animal models for studying multiple sclerosis. But to begin, here’s a brief summary of the developments at the MS Discovery Forum at msdiscovery.org.

 

In the progressive stage of multiple sclerosis, some astrocytes appear to upregulate genes that intensify inflammation and neurodegeneration. Researchers think that genetic changes cause astrocytes to release a fatty molecule that beckons inflammatory monocytes from the blood into the brain. A drug, miglustat, currently used in the treatment of Gaucher’s disease, may be a good candidate to repurpose as a drug to inhibit astrocytes from initiating this destructive process.

 

The so-called “long life” protein, Klotho, may hold the keys to remyelination. Named after the Greek goddess responsible for “spinning the thread of life,” an abundance of Klotho leads to longer lifespans in mice. The protein has also been associated with numerous age-related conditions such as Alzheimer’s disease. Recent research noted that reduced Klotho was associated with myelin degeneration in normal, aging Rhesus monkeys. A small molecule, currently known as ‘Compound A’ can promote Klotho in the CNS of mice, enhancing remyelination in the cuprizone mouse model.

 

We recently released a new data visualization comparing various characteristics – such as age, gender, and EDSS scores – across 74 clinical trials. You can look at each characteristic in every trial, or compare the means of all the trials. To view, go to the “research resources” tab at msdiscovery.org and click on “data visualizations.” Then click on “RRMS and CIS – Baseline Characteristics.”

 

[transition music]

 

Now to the interview. Dr. Hans Lassmann studies the pathogenesis of inflammatory diseases at the Center for Brain Research at the Medical University of Vienna in Austria. He met with MSDF at the MS Boston meeting in September to discuss demyelinating disorders.

 

Interviewer – Dan Keller

In terms of what we can learn from other demyelinating diseases, ones caused by infectious agents, how can this shed light on the processes and possible treatment of MS?

 

Interviewee – Hans Lassmann

That depends, obviously, on the models which we are looking. I think there is a major difference between multiple sclerosis and these other experimental models, because the experimental models which really induce large areas of demyelination always are associated with infection of oligodendrocytes. But in multiple sclerosis, there is actually no indication that oligodendrocytes are infected. Now this has consequences that also the demyelination is different in these experimental models because it follows the death of single infected oligodendrocytes. That means that lesions have, more or less, some sort of moth-eaten edges where single oligodendrocytes are falling apart with small pieces of demyelination in between intact myelin, whereas in multiple sclerosis the demyelination is a sharply demarcated lesion which does not follow the oligodendrocyte territories. What we, however, can learn from the models is the question how the brain handles an infectious process in the white matter with respect to inflammation and the amplification mechanisms of tissue injury in the demyelinating process. 

 

MSDF

So are they similar enough that we can discern something useful from it, even though the patterns do seem to differ in some ways?

 

Dr. Lassmann

Yes, we can. For instance, there is a major difference between the autoimmune models which we have and the virus models. The autoimmune models are predominantly mediated, or driven, by an MHC class 2 CD4-positive T cell response, whereas the virus models are predominantly driven by a CD8 T cell response. Interestingly, in multiple sclerosis, also the CD8 T cell response dominates. So we can actually learn a lot from these models on the mechanisms of CD8-mediated inflammation in the brain, and also on what are the consequences of a CD8-mediated inflammation in the brain with respect to tissue injury. 

 

MSDF

What about some of the diseases that are closely associated with MS but are distinct from it, like neuromyelitis optica and, I guess, concentric sclerosis and others, how do they shed light on things, if they do?

 

Dr. Lassmann

I think they shed a lot of lights on that. Let’s take first neuromyelitis optica. Here we are in a very favored situation because we know it is an autoimmune disease and we know the specific target antigen, and the specific target antigen is a water channel in astrocytes. So from that we have actually learned how antibodies against these astrocytes actually induce the tissue injury, in that case, by first destroying the astrocytes themselves, and then secondarily leading to oligodendrocyte destruction and demyelination, and also some axonal loss. So that actually is a perfect model for a scenario where T cells and pathogenic antibodies play a role in disease mechanisms, and that is apparently also the case in a subset of multiple sclerosis patients, but only in a subset. 

 

MSDF

How does the glia enter into this, both as a target and maybe as a mediator or effector?

 

Dr. Lassmann

Now, obviously, the prime target in multiple sclerosis is the oligodendrocyte and the myelin sheath, but there is obviously also pathology in other glial cells. There is an astrocytic pathology, and there is also a microglia activation and pathology in these cases. Now, the astrocytic pathology itself may also contribute to the lesion propagation because when astrocytes are also destroyed in the lesion, or primarily destroyed in the lesion, it will also secondarily lead to the oligodendrocyte loss and demyelination. This is a classical example of neuromyelitis optica. 

 

MSDF

Is that through mechanisms of macrophage activation, or debris, or mediator release, or toxic release?

 

Dr. Lassmann

No. From the astrocyte pathology, it’s so that the astrocytes and the oligodendrocytes are connected with gap junctions, and the astrocytes play a major role in supporting the energy demand of oligodendrocytes. So if you kill out the astrocytes, the oligodendrocytes starve to death.

 

MSDF

Now that you bring up energy, can we learn anything from mitochondrial diseases and their consequences?

 

Dr. Lassmann

Yes, here we can learn a lot because the mitochondrial injury and damage is in the center of neurodegeneration and demyelination in multiple sclerosis. In that case, in the disease the mitochondrial injury is apparently driven and induced by oxidative injury, but that it leads in a secondary consequence also to mitochondrial gene deletion, so to deletions of mitochondrially-encoded genes. And here the mitochondrially-encoded gene deletions are also present in many mitochondrial diseases, and for that, obviously, mitochondrial diseases are perfect models to study these aspects of multiple sclerosis pathogenesis. A key issue, for instance, is the mechanisms of mitochondrial quality control. Normally, it’s so that the damaged mitochondrion is just removed from the cell in autophagosomes. But this needs very specific mechanisms of recognition. If this quality control is actually missing or disturbed, then these damaged mitochondria can expand, can clonally expand, and then you get an upward cells having more and more and more damaged mitochondria. And that’s, for instance, also a mechanism which is very prominent in mitochondrial diseases. 

 

MSDF

Is that a failure of phagosomes? Is there a defect at that level?

 

Dr. Lassmann

No, I think it’s rather a defect in the mitochondrial proteins, because the mitochondrial proteins are expressed on the surface indicating the phagocytic system, whether they are intact or damaged. And when this process is more or less disturbed, then the phagosomes don’t recognize the damaged mitochondria anymore. 

 

MSDF

What are you doing now? What sort of paths are you pursuing in terms of these things that we’ve been discussing? 

 

Dr. Lassmann

We have in principles three major projects. The first is that we try to define more precisely what is the nature of the inflammatory response in multiple sclerosis and in to what extent this is different from what is seen in the respective experimental autoimmune models. Now, the second project deals with mechanisms of demyelination, and here the key question is there is soluble demyelinating factor in multiple sclerosis, but it’s not very clear what exactly the soluble factor is; it could be demyelinating antibodies, and that can be modeled in experimental models, like autoimmune encephalitis. But many data suggests that there must be other factors which are not immunoglobulin and not antibodies which are responsible for this demyelination. And then the third project deals with the progressive stage of multiple sclerosis, and here it’s the central pathogenic pathways, oxidative injury and mitochondrial injury. And our projects now go in the direction of what is the course of this massive oxidative damage in multiple sclerosis, how does that relate to mitochondrial injury, and what is the consequences then on the tissue with respect to energy deficiency and other things. 

 

MSDF

In progressive disease, do you see a shift towards more mitochondrial damage and oxidative damage or stress?

 

Dr. Lassmann

We have oxidative damage already in the early stages of MS, but in the early stages of MS the oxidative injury seems to be mainly driven by the inflammatory component; that means by inflammation, activation of microglia and then the production of reactive oxygen-producing enzymes. In the progressive stage of MS, we get additional amplification factors for oxidative injury, and they are related to brain aging and related to accumulation of lesion burden. So what we get, on the one hand, an age-related increase of iron in the human brain, and iron can massively potentiate oxidative injury by a reaction which is the so-called Fenton reaction. The second thing is that you have accumulated tissue injury in multiple sclerosis with retrograde and anterograde degeneration, and that leads to progressive microglia activation, which then can actually be transformed more easily in cytotoxic microglia cells by additional proinflammatory stimuli. And the third mechanism is that the mitochondrial injury increases, and in particular the mitochondrial gene deletion and the clonal expansion of defective mitochondria expand in the progressive stage with disease duration. And mitochondria, when they are damaged, they can liberate electrons, and the electrons can actually, again, react with oxygen, producing a reactive oxygen species. And so this is a more or less self-amplifying process which then leads to enhancement of neurodegeneration and demyelination. 

 

MSDF

Is there a role for glutathione here?

 

Dr. Lassmann

Yes. Glutathione is one of the key molecules for the oxidative injury, and obviously this is one of the players, but it’s only one. 

 

MSDF

It’s a player in the injury or in limiting injury?

 

Dr. Lassmann

That is not entirely clear yet.

 

MSDF

What have we missed or you think is important to discuss or add?

 

Dr. Lassmann

There is certainly in the multiple sclerosis therapy also the tests to increase remyelination and possible regeneration in the lesions, including stem cell therapies or increasing remyelination by soluble factors by cytokines and growth factors. This is all very interesting, but the key point is that as long as the disease process is active, newly-formed myelin is destroyed relatively quickly. 

 

MSDF

It seems that there’s almost an analogy to osteoporosis where it’s a balance between formation and destruction. Is there ongoing remyelination or turnover in the healthy brain?

 

Dr. Lassmann

Yes, there is a myelin turnover in the healthy brain, but there is also a profound attempt for remyelination in multiple sclerosis lesions. And what you see even in the early stages in very active MS lesions, you always find signs of ongoing remyelination. But, interestingly, in these early stages, really established remyelination is generally missing, and we have performed a study on that issue showing that if you have disease activity, the remyelinated areas are actually more prone to show new demyelination compared to the normal old myelin which is in there. So that suggests that this remyelination is present and all attempts are present, but this process is relatively instable as long as the disease process is active.

 

MSDF

Is there a thought of being able to inhibit that further, or accelerate a destructive process in these remyelinated areas?

 

Dr. Lassmann

I think this is not really specific for the remyelinated areas. If we are a [?], for instance, that disease process or the progression of the tissue damage can be stopped, for instance, with measurements making some sort of mitochondrial protection, or with certain antioxidative therapeutic strategies, then it will certainly be beneficial both for the old lesions and the newly formed lesions and the remyelinated lesions. But that’s more or less something which has to be solved before we can think of really effective remyelinating strategy.

 

[transition music]

 

Thank you for listening to Episode Seventeen of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations. 

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

[outro music] 

 

[intro music]

 

Hello, and welcome to Episode Sixteen of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with Dr. Revere “Rip” Kinkel about how to improve patient outreach. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

First, researchers are questioning if cognitive MS is a distinct entity. For some patients with MS, cognitive symptoms dominate over all other symptoms. Some of the symptoms could even be described as dementia. Researchers examined a small sample of this distinct subset of patients in a recent study in Clinical Neurology and Neurosurgery and found that many had severe brain atrophy and a high lesion load. While the results suggest that cognitive MS may be a distinct disease entity, the researchers are cautious not to draw any conclusions due to the small sample size and the weight of the term “dementia”.

 

An experimental oral agent for the treatment of relapse-remitting MS looks promising as it progresses through clinical trials. The drug, currently called RPC1063, was shown to be both safe and effective in a sample of about 200 patients. It may even be safer than fingolimod, which is currently the only oral drug FDA approved for the treatment of MS.

 

For women with multiple sclerosis, pregnancy is especially tricky. In a previous news synthesis, science writer and immunologist, Griselda Zuccarino-Catania, looked at many challenges for women with MS who are trying to get pregnant. But postpartum can be a tumultuous time for MS patients as well, since the risk for relapse increases after delivery. In this part of her series on pregnancy and MS, Zuccarino-Catania explores the current research on postpartum relapse risks, breast feeding, and disease-modifying therapies.

 

[transition music]

 

Now to the interview. Dr. Revere—or “Rip”—Kinkel is the director of the multiple sclerosis program at the University of California, San Diego. He is also the chief medical officer for an initiative managed by the Accelerated Cure Project, our parent organization, to establish an MS patient-powered research network. He sat down with me at the joint ACTRIMS-ECTRIMS meeting in Boston earlier this year to discuss how to improve patient outreach.

 

Interviewer – Dan Keller

Welcome, Dr. Kinkel. You are now interested in new models of care. What do these entail, and why do we need them?

 

Interviewee – Revere Kinkel

Well the traditional model is, of course, the patients coming into a clinic setting at a variable interval and having a diminishing amount of time to spend with a physician or any other kind of provider that they are seeing. Going forward in the future with fewer neurologists, fewer MS specialists available, we need to find ways to reach larger populations of patients. Whether that be through Internet portals, whether that be through outreach, through community clinics where we travel or whether it be through telemedicine or a combination of those things. So we are particularly interested in developing tools and models that allow us to reach patients in this way.

 

MSDF

What are some of the ways that you reach them: go out in the community or how do you specifically reach people who would not typically be contacted?

 

Dr. Kinkel

Currently we are doing a number of things. The first thing we have done is we have developed a virtual MS center online called HealthCareJourney.com which allows patients anywhere to sign up, ask questions relevant to their disease and the problems that they have and get answers. Both the questions and the answers are posted online for the entire community to see. We are also trying to find ways, particularly in California; this is true around the entire country, but particularly in California, to outreach to communities. What we have noticed with the transition with the Affordable Care Act is that a significant number of patients have been switched over to Medicaid programs. In our case we call it Medi-Cal in California. Many of these patients have been away from doctors for many years, off drugs for many years. They are not aware of services that are available to them. Many of them don't speak English as a primary language. We recognize the need to go out to the communities, have community outreach programs to reach these individuals, to do mini consults, tell them what kind of services are available, try to connect them to those services and then get them to come to our centers periodically and work with their local physicians.

 

MSDF

Do they typically respond well to this, or are they at all wary of what you are doing?

 

Dr. Kinkel

Well we haven't started doing it on a large scale basis. This is actually in the planning stages for next year. Interestingly we have kind of noticed this over time with drug company sponsored programs. So many of us will do these education programs for patients where we will go out and meet with a large group and we are always intrigued by the interactions we have one-on-one with the patients afterwards. That is when we really find out the issues they have and they start to hear about the things that are available for them and their eyebrows go up, they are interested, and you hear from them again because you can help them. That kind of setting has shown us that this kind of reaching out to communities helps. What I am talking about is going a step further; which is reaching out through community health centers, through other advocacy groups to find even less advantaged patients that might not have been even going to these kinds of programs and helping them, but also, including them in the process. Right now we have an understanding of MS that is based on a population that primarily goes to tertiary care centers, which is highly over-represented by Caucasian well-educated upper middle class individuals. We have far less of a knowledge of the needs and requirements of the less fortunate.

 

MSDF

Have you heard it all or can you discern anything from reaching out to these people and what they tell you that is either surprising or new?

 

Dr. Kinkel

I am totally amazed at kind of the lack of information they have. Just from basic MS-101. So you have to start there. Many of these individuals have kind of higher needs. When you have the needs of just putting food on the table and paying the rent and trying to make sure their children are safe, MS takes a back seat. Often in many of these families you see the effects of MS on the children, much as we see in all populations, but it is particularly acute on those individuals with less resources available to them. So there is a greater community need for support for these individuals both in terms of real services as well as in terms of education.

 

MSDF

What are you getting out of PCORI? First of all can you define what it is, and what sort of resources they can provide you?

 

Dr. Kinkel

PCORI stands for the Patient Centered Outcomes Research Institute, and the Accelerated Cure Project has a grant to develop a 20,000 patient centered research network. I am the chief medical officer for the PCORI Initiative. This will allow us to reach a large population of patients, but the challenge, much as I said a second ago, is reaching those individuals that might not even use the Internet or the web that often. So we need to find ways to not only include the traditional MS patients we see in many of the tertiary centers but also to reach out to these communities. What we intend to do with this reaching out is to get patients involved in the PCORI Initiative as one of the main things that we do when we reach out to the community. That will allow them a forum for describing their experience and potentially getting further resources available to them. 

 

MSDF

If they are not presenting to healthcare facilities, how do you reach them? Do you go to schools and get parents of kids or churches, or where do you get the word out?

 

Dr. Kinkel

One of the advantages that we have now when the law of the land is that everybody has healthcare insurance; is that we can actually track people. It is interesting. What happens in many communities is the physicians don't accept Medicaid for instance, some don't even accept Medicare. But what they do is they will accept this when patients are acutely admitted. The scenario that we hear over and over again is these patients go to a healthcare facility when there is some kind of an acute decline in function. They get taken care of. They have a diagnosis code of 340 for MS attached to them, but then they are discharged with no followup plans. They are actually not seen again until there is another acute decline in function. Well, we can identify them as soon as they are identified as a number 340. Once that is done, then we can reach them for these community outreach initiatives.

 

MSDF

Is this purely for diagnosis and treatment or can you do this for research? Do you get information from this?

 

Dr. Kinkel

What we do is we outreach to patients and provide education. We do not initiate a patient physician relationship without their approval. So you reach out to those individuals. There is no problem with that. They have to make the step of following through and initiating that kind of an interaction. They also have to make the step of deciding that they are willing to participate in something like the PCORI Initiative. All we can try to do is be as persuasive as we can and educate them about the benefits to both them as well as the greater society. 

 

MSDF

Do you find that there are people who don't even recognize a symptom? They just think their arm is numb because it must have been something they did at work and pass it off?

 

Dr. Kinkel

Oh yeah. It is an interesting phenomenon especially when things have been going on for a long time. If an individual is born blind, they don't see being blind a problem. If for the greater part of their life they have noticed that they have numbness in their feet, sometimes they don't mention it, because they don't consider it a problem. We always find that when we are seeing patients for the first time, they will describe these vague neurological symptoms that go back for many years. 

 

MSDF

Tell me about the OPT-UP project?

 

Dr. Kinkel

So the OPT-UP project is just a part of the normal evolution of the Accelerated Cure Project. The Accelerated Cure Project was developed to have a repository of well characterized patients with their biological samples for researchers around the country. We recognize that there were issues with the repository. We didn't have good longitudinal samples; we couldn't guarantee that we had samples on patients before and after they went on drugs so we could look at biological responses. So the OPT-UP study was to address that as well as the need to begin to create an environment where we were combining clinical and research activities to get more patients involved in research activities. By that I mean we know very little about long-term outcomes in MS. Part of this is because there is no coordinated manner to collect data longitudinally that is agreed upon between all of the clinicians that are caring for these patients. So we wanted to kind of operationalize that process so that we could follow these long-term outcomes and collect them. By doing so, we can answer a lot of questions that we have. For instance, in the near term with the OPT-UP study, since the only requirement for the study is that a person be initiating a drug, whether it be for the first time or for the tenth time, they are just initiating drug. One of the things that we will learn is; what are the reasons why people start drugs, what are the reasons why they stop drugs, what are the reasons why doctors are putting them on this drug or that drug. We know very little about that. What we really do know still is that a tremendous number of patients at least 50% discontinue a drug within two years of starting it. If we don't first know exactly why this behavior exists, it is hard to keep patients on therapies for a longer period of time, and to see which therapies are going to be most beneficial. 

 

MSDF

Will this go on indefinitely?

 

Dr. Kinkel

It is a long-term study. The duration of a study is always dependent upon a number of factors; funding, interest, but yes we are building in a number of mechanisms that allow us to follow patients for a very long time in the study. Probably the key to this is a dedicated nurse research coordinator at each site that will be responsible for entering and following patients over a period of time. And when sites exceed a certain number of patients then they hire another one, because what we have discovered in the past from the many research studies that we do is there are competing interests. Whenever we try to continue to follow people for a long time, other interests win out. There is no one there to kind of encourage the patient to continue their participation. The studies that have been more successful – a long-term study like the Nurses' Health Study – they are able to do that primarily because they put the resources into ensuring that, that experience is meaningful for the patients and that they will want to continue to contribute that data.

 

MSDF

Will this initiative also collect general health data knowing about comorbidities and be able to correlate those with the course of the disease?

 

Dr. Kinkel

Yes absolutely. It is one of the main things that we want to do. In fact, one of the reasons why pretty much the only inclusion criteria is, that a person be starting a drug. Most Phase III studies exclude people when they have other health conditions. This is why there is so little external validity to these studies. The way we gain that validity is to encourage those patients who do not normally contribute to clinical research to participate in the study, either because they don’t want to, they can't get to the site, or because they are excluded by the exclusion criteria.

 

MSDF

On these topics, is there anything important to add?

 

Dr. Kinkel

I think the most important thing to add is that we are entering into an era…we are already in an era in which technology is rapidly transforming how we reach patients, and we need to kind of embrace it. I see that many of my colleagues are reluctant to. I see it in their unwillingness to embrace electronic medical records for instance. They see it as a burden. 

And it is true; there is some burdensome aspects to it. I believe, however, in a world in which they have less time to spend individually with their patients in a clinic setting, in that kind of a world, they need to find other mechanisms to reach and meet those needs of their patients. One of the ways to do that is through these kinds of technologies. Using the website. I encourage them to send their patients to the healthcarejourney.com website for instance to get general information about MS so that they can reduce the burden on their own centers and their own staff with patients calling in with questions every other second.

 

MSDF

Very good. I appreciate it.

 

Dr. Kinkel

Thank you.

 

[transition music]

 

Thank you for listening to Episode Sixteen of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations. 

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

 [outro music]

 

 

[intro music]

 

Host – Dan Keller 

Hello, and welcome to Episode Fifteen of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with Professor Ludwig Kappos about a recent head-to-head clinical trial of the experimental drug, daclizumab, versus interferon. But to begin, here's a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

We recently released a news synthesis by science writer, Carol Morton, that goes along with this podcast. The article is all about daclizumab, its history, and the recent results of the phase 3 clinical trial. The results of the clinical trial show that the drug is better than interferon at reducing disease activity in patients with relapsing-remitting multiple sclerosis. Surprisingly, recent research suggests that daclizumab works by natural killer cells to target autologous T cells. It may also work in two more unusual ways—go to our website to read the whole story.

 

Antibodies to myelin oligodendrocyte glycoprotein—also known as MOG—may play a role in a subset of patients with neuromyelitis optica spectrum disorders according to several labs in Europe and Asia. At the ACTRIMS-ECTRIMS meeting in September, several of these labs presented data that showed patients who test positive for the MOG antibody had a very different clinical phenotype from the majority of NMOSD patients who have an antibody to a different protein, called aquaporin-4. The findings could mean that anti-MOG-positive patients represent a distinct disease subgroup.

 

Recently we’ve added quite a few items to our meetings and events page. From webinars to large annual meetings, there’s an event for everyone’s schedule in the remaining months of 2014 and well into the summer of 2015. Go to msdiscovery.org and click on the “professional resources” tab. From there, click on “meetings and events” to view all the items. And if you have a meeting you’d like us to list, please send the information to editor at msdiscovery.org. Hardly any meeting is too small. We’re even willing to list local departmental seminars.

 

[transition music]

 

Now to the interview. Professor Ludwig Kappos is the chair of neurology at the Neuroscience Network at the University of Basel in Switzerland. He met with me at the 2014 international ACTRIMS-ECTRIMS meeting in Boston to discuss the findings of the phase 3 DECIDE trial of daclizumab versus interferon. Daclizumab is a monoclonal antibody against the alpha subunit of the interleukin-2 receptor. 

 

Interviewer – Dan Keller

Welcome, Professor Kappos. Let's talk about the study you're presenting here at ACTRIMS on daclizumab. What was the aim of the study?

 

Interviewee – Ludwig Kappos

The aim of the study was to position this compound in relation to an established treatment with interferon and to see if these positive effects that had been observed in studies where it was used as an add-on to interferon or as compared to placebo if these also stand in comparison with interferon. 

 

MSDF

How did you go about it: methods, interventions, patient population?

 

Dr. Kappos

It was double-dummy controlled, parallel group study lasting a minimum of two years per patient in a population of active relapsing-remitting multiple sclerosis. And patients were randomized equally either to daclizumab once per month subcutaneous or to interferon beta-1a once a week intramuscularly and received dummy injections in order to keep the blind. 

 

MSDF

How did you decide on a once monthly dose for the daclizumab?

 

Dr. Kappos

That was the result of previous studies where it had been shown that this once monthly dose is sufficient to achieve the effects that we expected to see. 

 

MSDF

Because it's a monoclonal it has a long pharmacokinetic profile. Is that right?

 

Dr. Kappos

This is something that is shared also with other monoclonals. The advantage here is that you can apply it subcutaneously; they don't intravenous infusions like, for example, with natalizumab.

 

MSDF

What did you find?

 

Dr. Kappos

The primary outcome was reduction in relapse rate, and as compared to interferon beta-1a, it do add to a reduction that was close to 50%. 

 

MSDF

What about a proportion of patients experiencing relapse?

 

Dr. Kappos

Again, there was a significant reduction, and the curves separated already after the first half year. So the effect was relatively early. 

 

MSDF

And what about some of the imaging? What did you find on MRI and how about patient disability?

 

Dr. Kappos

Yeah again, as compared to interferon, it had a much more pronounced reduction of inflammatory activity, as depicted by T2 lesions or gadolinium-enhancing lesions in the scans during the study. And it also had an affect on T1 hypointense lesions that were reduced as compared to interferon. And interestingly enough, although it had a more pronounced antiinflammatory activity also in early and over the whole duration of the study, positive affect on brain volume loss. 

 

MSDF

It appears that in both groups about 30% of the people discontinued. Were there any differences in reasons or couldn't you discern that?

 

Dr. Kappos

Overall there was a similar incidence of adverse events, but there were somewhat more serious adverse events and adverse events as a reason for discontinuation. This was mainly related to cutaneous side effects; so rashes itching that in some cases needed discontinuation, in others could be treated sufficiently with ongoing medication or resume medication with steroids.

 

MSDF

This was not just local infusion reactions but more generalized skin reaction?

 

Dr. Kappos

They were independent of the injection site; so they did not occur at the site of injection but in other parts of the body.

 

MSDF

Is there an explanation in terms of IL-2 for that, or was it just sort of idiopathic?

 

Dr. Kappos

Of course, you would expect that this regulation of the immune system has this effect perhaps in the interaction of innate and adaptive immune system, but it's not yet clear what it means. The fact is that we didn't see other autoimmune diseases of relevance, only of increased incidence, and therefore it must be something unique to the skin. And fortunately, it's usually quite well manageable. 

 

MSDF

Is there a role for biomarkers? Can you discern anything here where it would indicate that you should use one drug versus another? Does daclizumab have anything unique about it that you can follow? 

 

Dr. Kappos

In the previous studies, we had had the observation that a certain subpopulation of immune cells – the so called CD56bright natural killer cells – are increased after initiation of treatment in those patients who seem to respond better to the drug. In this study, this response was seen in nearly all patients, and therefore it doesn't seem to differentiate good responders from perhaps not optimal responders. We have not finished the evaluation, and there were a series of biomarkers that had been evaluated during this trial. So I hope that we still will be able to find something.

 

MSDF

In the oncology arena, sometimes adverse effects actually correlate with good efficacy. Did you see anything like that here?

 

Dr. Kappos

No, there was no increased efficacy in those with cutaneous reactions, and otherwise the drug did not create problems. So you would not expect on a regular basis to experience adverse events. It's a different case than, for example, as compared to interferons where you have a very high frequency of flu-like symptoms. This is not the case here. So usually you would not realize, except for the injection that happens, that you take the drug. 

 

MSDF

Would there be any use to having a combination arm in a trial like this – interferon plus daclizumab?

 

Dr. Kappos

The first studies had been as an add-on to interferon and have shown an effect as compared to interferon without this add-on, without daclizumab. At the moment, yes, it would be something that could be followed, but I don't really see what the ideal combination would be and then not really the necessity for this drug in contrast to other drugs that have similar or lower grades of efficacy.

 

MSDF

I know it wasn't included in this trial, but can you compare the efficacy of daclizumab with anything currently available that people use?

 

Dr. Kappos

I think it's very difficult to tell because it's always a problem to compare across studies because of different methodology; even the selection criteria formally are very similar may result in different populations of patients. So I would say from the grade of efficacy that was achieved it is certainly at least at the level of fingolimod or dimethyl fumarate. How it relates to natalizumab; if it could be used in patients who stopped natalizumab? These are questions that will have to be explored in the future.

 

MSDF

Will you follow these patients further to see if there are any late effects either positive or negative?

 

Dr. Kappos

Yes, most of them are in the extension studies and had the option to continue with open-label daclizumab. I think it's approximately 80% or more of the patients who decided to continue in this followup, and we will have a long-term followup for another four or five years.

 

MSDF

From all of what you've said, what you make of this in terms of clinical significance, in terms of the future of this compound?

 

Dr. Kappos

Well I think that it deserves to be approved and also to be one of the available options that we will have in the treatment of relapsing multiple sclerosis. If it has also an effect on progressive disease is something that my personally would be interested to know more about.

 

MSDF 

Is there anything important to add that we haven't discussed?

 

Dr. Kappos

The data now are consistent with a good data that were derived from the placebo controlled SELECT trial. And we have to take into account that they are against one established drug with approved efficacy. So it's more than that, and that's, of course, encouraging. 

 

MSDF

I suppose anything that gets you away from the side effects of interferon are a good thing.

 

Dr. Kappos

Yes, anyway, of course, most other drugs that get you away from the side effects of interferons. But it seems, except for these cutaneous, manageable side effects, it seems also to be well tolerated. So a drug that could be used with a low threshold. 

 

MSDF

Is there tachyphylaxis? Does that side effect go away, or you just have to keep treating it the cutaneous?

 

Dr. Kappos

It was different. It seems to be the case that if we had treated initially with steroids and then do not wait too long then it recovers, and then you can also resume treatment, or you can continue treatment. But there are the cases where we didn't continue treatment and then it result, but we didn't start again.

 

MSDF

Very good. I appreciate it, thank you.

 

Dr. Kappos

Thank you.

 

[transition music]

 

MSDF

Thank you for listening to Episode Fifteen of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations. 

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

[outro music]

 

 

 

 

 

[intro music]

 

Host – Dan Keller

Hello, and welcome to Episode Fourteen of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features part two of an interview with Professor Gavin Giovannoni about the role of Epstein-Barr virus in MS. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

We've published a blog post from Christine Granfield, the founder of HealthCare Journey. Healthcarejourney.org is a website designed to help MS patients easily navigate the expanse of information about MS. In the blog post, Ms. Granfield says that HealthCare Journey is not meant to replace the doctor-patient relationship but instead provide a place where patients can find answers to questions with accurate, up-to-date information when their physician might not be available.

 

We published another blog post written by our intern, Cynthia McKelvey, on how to interact with the news media. News about science is often sensationalized and over simplified. But that’s all the more reason for researchers and clinicians to be media-friendly. In her post, Cynthia offers 13 tips on how to talk to reporters so you can be sure the best and most accurate information gets to the public.

 

Last week we interviewed Dr. Alan Thompson of the International Progressive MS Alliance about the difficulties of researching progressive MS. We published more information on the Alliance, its goals, and a full list of the 22 recipients for their first round of funding, totaling 22 million euros. To view the article, visit msdiscovery.org and visit our News Briefs section under the News and Future Directions tab.

 

[transition music]

 

Now to the interview. Professor Gavin Giovannoni from Queen Mary University in London is one of the worlds most prolific and most visible MS researchers and clinicians. He's also on the scientific advisory board for MSDF. Two weeks ago we featured the first part of my interview with him about the potential for a cure in MS. This week we’re going to discuss the roll of EBV in MS.

 

Interviewer – Dan Keller

Professor Giovannoni, where does it come in? How has it entered the thinking?

 

Interviewee – Gavin Giovannoni

We have a causal theory. We don't just switch on a light switch, and we've got a call that said it evolves over time. And if there's one particular thing that looks like it's got the top candidate for being a cause of MS is Epstein-Barr virus. And I think the original observation is epidemiological. People with infectious mononucleosis, which is delayed EBV infection that is symptomatic, have a higher risk of developing MS, and that's been reproduced now across many, many studies as a risk factor. But EBV infection in itself is a risk factor because if you're not infected with the virus, in other words people who don't have the virus, have a very, very low risk…it's almost a zero risk of getting the disease. So in terms of its negative predictive value – that's the strongest value we have – people don't get MS if they don't have EBV. So it looks like it’s an essential component of the causal pathway. How it's acting in the causal pathway? We don't have any idea. We just do know that if you do get EBV infection or infectious mono it's a risk factor throughout life. So in the Danish study, it shows the risk remains even when you go into your 40s, 50s, and 60s, which is interesting.

 

And EBV is a complex biology. We don't know where it's acting. We know it resides as a latent infection in the B cell. And what it's doing to B-cell biology is incredibly complicated. It hijacks B-cell biology, and it affects its antigen-presenting function, it affects its survival, etc. So people are targeting the B cell; I think the B cell is important. And the reason why I think the B cell is important when you look at all the most effective therapies in MS, when you put them on a chart with all the cells they affect, the only common cell to all of them is the B cell. And the link that the B cell may be the Epstein-Barr virus. And how EBV triggers autoimmunity haven't a clue. We originally thought well maybe the link between infectious mono and MS was related to HLA susceptibility. But we did a study on university students in the UK, and we showed that the HLA type that predisposes you to infectious mono is not the HLA type that predisposes you to MS. So we don't think it's at the HLA level that EBV is interacting with MS susceptibility; it's somewhere else.

 

The other risk factors are smoking. And when you start putting smoking and EBV and low vitamin D, which is the other environmental factor, together it looks like there's some interaction of all three components. But how they're working at a biological level that's where research needs to be done. So some people are … I think there's mimicry between EBV and myelin proteins, and there is some data that there are some antigenic epitopes in the EBV proteins and [?] antigens, which is why a lot of people are focused on CD4 cells as being the link. I'm not sure if it is the CD4. Others are focused on the CD8 cells as being the link. Michael Pender in Brisbane, Australia, thinks that Epstein-Barr virus is acting as the innate stimulus, the danger signal, that just upregulates innate immunity that then allows autoimmune responses to occur on top of that. And he thinks that's occurring in the central nervous system. That's his theory. And he thinks that people with multiple sclerosis have a deficiency of cytotoxic CD8 cells that keep the EBV virus in check. So he's now testing the strategy of trying to boost the CD8 response against EBV and kill the Epstein-Barr virus to lower the innate activation and reduce autoimmunity. That's his theory.

 

I wish I could tell him my theory. All I know is that the epidemiological observations are pretty standing. And you know, we probably should be doing a vaccine trial to test the hypothesis. There is a vaccine for EBV, but it's been discontinued. So GSK developed the vaccine. It wasn't that effective in stopping EBV infection, but it was very effective in preventing infectious mono. So what it did was it raised your immunity to a level that stopped you getting infectious mono, and that may be enough for MS prevention. You know, when they sold the EBV vaccine program to MedImmune, and I heard about six months ago that maybe they had stopped the program. There is no EBV vaccine program occurring in the pharmaceutical arena. There's been a recent meeting in Oxford around Epstein's anniversary because it's 50 years since he discovered the virus. And the, Harold Varmus was there, and there's a big push now for the NIH to fund a vaccine study – interesting not to prevent MS but to prevent the secondary malignancies linked to EBV. Because EBV is linked to a whole lot of hematological malignancies. So the idea there would be if you could prevent people getting Epstein-Barr you prevent a whole lot of lymphomas particularly. I'm personally a little worried about that strategy because EBV is one of our most co-evolved viruses. At a population level, it's part of our immune systems. So I actually think at a population level EBV must be doing something good for society and the population. I think it may be a link to B-cell memory or something like that.

 

So if we stop people getting EBV, we may be storing our problems at a population level. But until we do the trials we won't know. So we need a vaccine, and that's the way to test is EBV causal? Coming away from it, it may just be the trigger, or it may be driving the disease continuous. If that's the case, then we need to have anti-EBV drugs. And there is one being tried right now; it's called ocrelizumab. It's an anti-CD20 drug. Itself hasn't been tested as an anti-EBV drug, its predecessor, which is rituximab, is licensed as an anti-EBV. It's actually the only drug that's licensed to treat EBV. It's licensed to treat EBV associated lymphoproliferative disease, which occurs in transplant patients. It's pretty effective at switching off on that condition, and the EBV levels just plummet. A company that's developing ocrelizumab, which is Genentech Roche, wouldn’t like for me to say that it's an anti-EBV drug, but that's exactly how it may be working in MS; it may be targeting EBV. The obvious thing is to test antivirals that target EBV. There are no specific ones that have been designed for EBV, but we've got a particular drug that we would love to test against EBV because it has some activity. Trying to get the funders convinced that we should do a trial of an anti-EBV drug in MS has been difficult. I think we shouldn't ignore the EBV hypothesis, though, because the data out there is pretty compelling that it's causal. And as a community, I think we have a responsibility to test whether or not it is causal. And the only way we can do that is intervention studies – vaccines and targeting the virus with antibiotics.

 

MSDF

It seems the geographic distribution of MS may actually be opposite say the distribution of Burkitt’s lymphoma. And what is EBV doing and how does it do it in different regions? And I wonder if that brings in the vitamin D hypothesis again.

 

Dr. Giovannoni

MS prevalence pretty much matches infectious mono prevalence. So infectious mono has also got a gradient. The Burkitt's lymphoma thing probably that follows patterns of parasitic infection, particularly in malaria. So I think EBV probably interacts with other infectious agents, and that's one of the theories about EBV; it's not working on its own; it's working as a coinfection with another virus. The other virus that we need to talk about are the family of the HERVs, human endogenous retroviruses. Because the EBV is a potent transactivator of these viruses. In the big body of literature on HERVs being involved in MS, a lot of us think it's associative. In other words, inflammatory response triggers transactivation of HERVs in what we see as an epiphenomenon. But there are people who think it may be linked to the cause of the disease. Again the only way we can test this hypothesis is by treating people with drugs that target EBV and HERVs. Because HERVs are drugable; they are retroviruses, and you've got a whole arsenal of therapy that could target the various components of HERV biology. We should be doing trials in that as well.

 

Coming back to the vitamin D, there has been one small study that needs to be reproduced showing that if you do get EBV infection when your vitamin D levels are low your antibody responses are much more marked. And so there may be some link between low vitamin D and infection, but nobody has actually studied that formally, and I think it's something we tried to do with our epidemiological tools to see vitamin D deficiency or low levels makes it more likely that you're going to get infectious mono, that maybe they are interacting with each other. I don't think it's going to be as simple as that, though, to be honest with you. I think they're probably going to be working in an immunological level. I'm not sure if they're going to be causal; I think they may be associated with each other. EBV triggers a mess of lymphoid proliferation, which consumes vitamin D levels. So if you find someone with infectious mono and they have low D levels, it could be the infectious mono is reverse causation rather than the other way of causation. So we need to do that prospectively, and it's a difficult study to do.

 

But I think also the other thing you've got to look at is when they're starting to put all of these risk factors together in studies, and this has been mainly been done in the Scandinavian databases – and you start putting the HLA-DR15 in, the protective HLA-A2 in, the history of infectious mono, serum levels of anti-EBV antibodies, put smoking in, start putting vitamin D levels in – you're beginning to see relative up about 40. So that's a big signal to me because the doyen of causation theory, Bradford Hill, said that when you start getting relative risks above 40 that you should be thinking causation. So I'm beginning to see a causal pathway where all of these factors now are giving relative risks that are very high compared to the background population. And so, those factors must all be in the causal pathway. And the question is which one can you intervene in? And there's a few you can intervene in. But EBV is the obvious one. If you take it out of the causal pathway, you may be able to prevent this disease.

 

So I'm lobbying – and whole lot of us are lobbying – that we really need to get the public health community and the MS community and the virology community together so we can start thinking about prevention trials. Around about 5 to 10% of the adult population are EBV negative. But that group of people don't get MS. So that's the important factor is those people don’t get MS.

 

MSDF

But the flip side is 90% of the population has been exposed to EBV, and most of those people don't get MS. So do you think it's all of these other cofactors you've mentioned? Whereas EBV sort of lights the fire if the fuel is there?

 

Dr. Giovannoni

Yes, I think that's true. And Bradford Hill, I mean he developed his theory for causation around common manifestations or re-exposures. Like asbestosis is one of the examples he always used that if you had asbestosis, which is quite of a rare exposure, the chances of getting mesothelioma, which is a rare cancer, was almost 200 times background. So that's easy to understand. But EBV is such a common exposure, and MS is a relatively rare manifestation. So in that situation, the relative risks come down. So even though the relative risk of getting MS is only about 2.2 to 2.5 with infectious mono, it doesn't mean to say it's not causal. It could still be causal. So I'm not worried that the relative risks are low. But I agree with if it's EBV infection on top of something else the genetic susceptibility, the low vitamin D, or all those other factors that then triggers the autoimmune response.

 

But if EBV is a pivotal factor and you stop it, those other factors are irrelevant. That's why we need to do prevention studies. We need the vaccine, though. The original vaccine strategy was developed to prevent EBV completely; that's in terms of oncoprevention. But in terms of MS and autoimmunity, you may not have to prevent Epstein-Barr virus. Maybe what you need is to make sure you're vitamin D replete and get wild-type infection when you're very young. That may be sufficient to lower the risk of MS. You may not necessarily need a lifelong protective immunity against Epstein-Barr, but maybe you just need to be infected at a young age when your immune system can deal with it. It doesn't fertilize the field for autoimmunity later on in life; that may be the strategy.

 

MSDF

Does it get into the possibility of tolerance?

 

Dr. Giovannoni

Yes.

 

MSDF

To EBV?

 

Dr. Giovannoni

If we knew about the biology of EBV, I mean I'm not a virologist. And when I delve into the complex biology of Epstein-Barr virus, how it's fooling the B cell into surviving longer and bypasses B-cell signaling pathways, it's a credibly cleaver virus. And there's a lot of biology there that needs to be picked apart in the MS field. So there may be pathways in the EBV biological pathway that could be targeted rather than just targeting the virus itself. So I think there's lots of research to be done. This is why we, as an MS community, really need to bring virologists into the community as much as possible. And at the moment, that doesn't seem to be happening a lot. There's very few virologists interested in MS. You can count them on one hand to be honest with you that are really interested in MS. Most virologists are working on other diseases. And when you go to them, it's hard to get them interested in MS because MS is something on the periphery of their thought. They're usually targeting obviously infectious diseases. But most of the EBV virologists are working in oncology, lymphomas.

 

MSDF

Very good. Thank you.

 

[transition music]

 

MSDF

Thank you for listening to Episode Fourteen of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

[outro music]

 

 

 

 

 

[intro music]

 

Hello, and welcome to Episode Thirteen of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with Dr. Alan Thompson about the International Progressive MS Alliance, a new collaborative effort to unravel the mysteries of progressive MS. But to begin, here is a brief summary of our time at the ECTRIMS-ACTRIMS meeting in Boston.

 

The M-S-D-F editorial staff was in full force at MS Boston 2014. We were everywhere covering talks and poster sessions, tweeting up a storm. We live-tweeted the Plenary sessions and most of the talks. If you missed the, or just want to relive the highlights, you can see a roundup of all the best tweets from MS Boston 2014 at our blog on msdiscovery dot o-r-g.

 

At the meeting we recorded several interviews for future Multiple Sclerosis Discovery podcasts. We’re excited to bring you interviews with researchers, [Dan, name three people you interviewed], and more over the coming weeks and months.

 

Our parent organization, the Accelerated Cure Project for Multiple Sclerosis –ACP--, also had a booth at the meeting. We really enjoyed meeting many of M-S-D-F’s readers and listeners and telling them more about our organization and our projects. In addition to MSDF, ACP manages a repository of almost 3,000 biological samples from people with Multiple Sclerosis (MS) and other demyelinating diseases, their affected and unaffected relatives, and unaffected, unrelated matched controls. We provide the samples to researchers quickly and at minimal cost. ACP has received funding for a patient-powered research network for multiple sclerosis. We will soon debut the network’s web portal, called iConquerMS. We were especially delighted to announce initial funding from EMD Serono for OPT-UP – which stands for optimizing treatment, understanding progression -- a longitudinal study of 2,000 people with MS. If you missed us, visit accelearatedcure dot o-r-g for more information.

 

[transition music]

Now to the interview. Dr. Alan Thompson is the chair of the scientific steering committee of the International Progressive MS Alliance. At the ECTRIMS-ACTRIMS meeting, the Alliance announced their 22 first-round grant recipients. Dr. Thompson met with science writer Cynthia McKelvey to discuss the challenges in researching progressive MS.

Interviewer – Cynthia McKelvey

What is the goal of the Progressive MS Alliance?

 

Interviewee – Dr. Alan Thompson

The goal is very simple; it’s to find treatments for progressive MS, probably the most important thing we have to do in the field of MS now.

 

MSDF

We’re at the ACTRIMS and ECTRIMS meeting in Boston, and tomorrow you’re going to announce the first round of grant recipients. What were you trying to accomplish with this first round?

 

Dr. Thompson

Well this, the RFA one as we call it, was really to stimulate interest in progressive MS; so to encourage as many people around the world to put in applications for these relatively small awards – they’re 75,000 Euros – but it was really to stimulate interest. And it certainly succeeded in doing that in that we had 195 applicants, perhaps double of what we thought. And I think what’s also quite unique about this is this is an international initiative, so the review of these awards was done internationally and agreed by this panel, so that they’ll be announced tomorrow. We were initially hoping we would have 15 awards, but we’ve been able to make 22 awards because of A, the quality of the applications, but also the willingness of the executive committee to actually go a little bit further.

 

MSDF

With this first round in terms of the research, what do you hope to accomplish to eliminate some of the mysteries in progressive MS?

 

Dr. Thompson

We’ve identified a number of areas that we feel are absolutely critical if we’re going to actually identify new treatments. The first is around mechanisms underlying progression and thereby identifying potential targets for treatment. Then, of course, there’s the whole issue of biomarkers and evaluating the effect of treatments, setting up new trials in progressive MS. And the other area is around rehabilitation and symptomatic management, which is really critical for people with progressive MS.

 

And if you look at the range of awards that we’re making, they actually hit all of these areas. So there’s a couple of awards in each one, which is really very reassuring. I mean, I think the hope will be that these could also be the beginning of the major network awards that we’re moving on to in the next phase.

 

MSDF

And my understanding is that in progressive MS, there’s a lot of issues just in doing basic research, and even in moving onto clinical trials. What are some of those issues and how do you propose that research can overcome them?

 

Dr. Thompson

Well, if we look at two areas, I suppose, the first is understanding the basic mechanisms, and what does progression mean, what’s actually happening? Is it driven by inflammation, is it purely neurodegenerative, what’s the combination of those, are there other cells involved like microglia or astrocytes? So there are big questions around mechanisms, which are essential if you’re going to target treatments. And driving that research forward will help us to define new targets. That’s part of the story.

 

The other large area is then, well, how do you measure effect? And progression goes on over many, many years, it is predominantly neurodegenerative so we need to think about different biomarkers; markers of tissue loss or tissue destruction rather than of inflammation, which is, in many ways, much easier and which we’ve been able to apply in relapsing-remitting MS. So that needs to be resolved. And there’s a lot of imaging work going on, and, indeed, other CSF biomarkers being looked at which might help us in that field.

 

And then going on to trials themselves. The current approach to trials is very lengthy, very costly, and not very innovative. And we need to think about news ways of looking at a number of different agents at the same time. And there are already examples, both in Europe and in the United States, where we’re starting to do that. So these are all areas where there’s movement. And I suppose what the Alliance has tried to do is really drive that, focus it and drive it forward in a true collaboration.

 

MSDF

So there aren’t currently, at least in the US, any FDA-approved treatments for progressive MS. What specific types of treatments are you focusing on that you think will be most promising?

 

Dr. Thompson

The treatments we have at the moment which we are you using in relapsing-remitting MS are fundamentally around suppressing inflammation, and that does not appear to be sufficient to have an effect on progression, and that’s probably not surprising. So I think the kind of approaches that we need to take with progression is around neuroprotection and also around repair. And these are more challenging; these are more challenging from a neuroscientific point of view, but also more challenging clinically. But that’s where we would expect the new trials to come out of those areas, particularly around neuroprotection.

 

MSDF

Why is it challenging to study that scientifically?

 

Dr. Thompson

Well, because neuroprotection is a concept at repair that we’re thinking about, not just for MS but for a whole range of neurological conditions, including Alzheimer’s, a motor neuron disease. And it’s challenging because you have to understand the underlying mechanisms and then you have to understand how your intervention is going to alter those. And that’s really getting to the heart of some of the most difficult questions in neuroscience.

 

MSDF

It’s also my understanding that even just confirming that any of these drugs actually work in people is another challenge.

 

Dr. Thompson

Yes. I mean, I think confirmation requires, first of all, a really reliable surrogate marker, but it also requires a clinical measure. And when you’re looking at a process which goes on over 30 years, trying to get a snapshot in two or three years is very difficult. And the clinical measures we have in MS are not very sensitive to change, and so there’s another major initiative called MOSAIC which is actually looking at trying to develop more sensitive measures that we could then apply in trials for progressive MS.

 

MSDF

What is the future for the Progressive MS Alliance? How do you propose to go from this first round of grants towards a cure?

 

Dr. Thompson

The Alliance is a new concept, and the idea of everybody working together internationally to solve a really difficult problem is very exciting. The RFA-1 was encouraging because there was so much interest. So it’s quite clear that in every country from North America to Australia, Europe, Asia, everybody feels this is the key question. So what I would like to see happening is we moving from these smaller grants to this international network of grants. So the RFA-2 will require major centers to come together to address very specific questions. Collaboration is the key for difficult questions, so I think this is the right approach.

 

We’re planning RFA-2 to be very iterative with the scientific steering committee so we can really try and get the very best out of it. This has to be transformational. If RFA-2 is successful and we’re putting three or four major pieces of research forward that will be costing between 4 and 5 million Euros, then we might think about building on that and becoming even more ambitious, drawing in even more resources internationally. And then perhaps – and hopefully – and the final aim, coming up with a treatment for progressive MS.

[transition music]

 

Thank you for listening to Episode Thirteen of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

 [outro music]

 

 

 

 

[intro music]

 

Host – Dan Keller

Hello, and welcome to Episode Twelve of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with Professor Gavin Giovannoni about the potential for finding a cure for MS. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

Monocytes and microglia are hard to tell apart and as a result, their roles are poorly understood in MS. But we recently covered a paper that demonstrated separate roles for these macrophages in EAE. Using fluorescent tags, the researchers were able to determine that monocytes were directly attacking the myelin. Meanwhile, microglia arrived to the same area of myelin attack only to be shut down. The paper has major implications for future methods in studying MS as well as for the mechanisms of the disease itself.

 

We published another data visualization recently, titled the “MS Galaxy.” The visualization shows 250 authors of phase 3 clinical trials in MS, and how they are connected to each other. You can explore the galaxy by visiting msdiscovery.org and visiting the data visualizations section under the “research resources” tab.

 

Additionally, we published a different sort of visualization. This one is an animated video that synthesizes the current understanding of MS immunopathogenesis. Often in presentations, immunologists will toss up a confusing slide covered in shapes, arrows, and acronyms. ACTRIMS’ president, Dr. Suhayl Dhib-Jalbut, has taken that slide and broken it down into its component parts. It’s a wonderfully illuminating experience to listen to him go through the slide step-by-step. MSDF worked in collaboration with Dr. Dhib-Jalbut to make the video. You can view it in the data visualizations section of our website.

 

[transition music]

 

Now to the interview. Professor Gavin Giovannoni from Queen Mary University in London is one of the world’s most prolific and most visible MS researchers and clinicians. He is also on the scientific advisory board of MSDF. I met with him at the university to discuss the potential of a cure for MS. This is part one of the interview. Next week’s podcast will feature part two, in which Professor G, as he’s known, discusses the role of Epstein-Barr virus in MS.

 

Interviewer – Dan Keller

Professor Giovannoni, let’s talk about the possibility of cure of MS. I suppose the first question would be what would you define as a cure?

 

Interviewee – Gavin Giovannoni

Because MS is considered to be an autoimmune disease, we should really be able to destroy the autoimmunity by replacing the immune system, or rebooting the immune system, that’s the concept. And there are certain drugs that do that. Obviously, the most aggressive would be bone marrow transplantation, this autologous bone marrow transplantation. And the other one is a recent drug we’ve been using, alemtuzumab, which is a drug that targets leukocytes and depletes them and allows the immune system to repopulate, and when repopulated comes back clearly in a different way. And hopefully those two strategies will remove the autoimmunity. And those two strategies are very effective.

 

A significant proportion of the people who are treated with bone marrow transplantation or alemtuzumab go into long-term remission; I’m talking about remission 10, 12, 15 years in some of these patients. And if you follow these people up, there’s no evidence of inflammatory activity, so they don’t have relapses. And you monitor their MRI scans, you don’t see any new lesions; the lesions that are there are stable, scarred lesions. And also if you monitor the end-organ brain atrophy rates are not accelerated, their brains are shrinking in the same range as in normal aging. You know, looking at it at a superficial level, we can’t find any evidence of active MS.

 

Now the question is are those people just in long-term remission or are they cured? And so the definition of a cure then is how long would you follow these people up and say, alright, your MS has gone away. We’ve been debating this in the field for a while. And we think a reasonable definition would be 15 years after they’ve had the treatment, and that would give us sufficient time to study a population and compare them to what we would expect to happen in a natural history study or other treatments. And it’s looking like a significant number of these people are staying in long, long-term remission. So I’m hoping that a portion of them will be cured of the disease.

 

MSDF

Now these are autologous bone marrow transplants?

 

Dr. Giovannoni

Yes.

 

MSDF

So what would prevent them from re-reacting to whatever caused their problem in the first place? I can see allogeneic transplant, you would have a sort of non-susceptible population of cells.

 

Dr. Giovannoni

Yes. I mean, we don’t really know the pathogenesis of autoimmunity in the sense where’s it driven from. I mean, there’s lots of epidemiological evidence in the MS field it probably starts in utero, actually. There’s evidence for parental origin, and migration studies, and monthly birth defect, etc., to suggest that something’s happening in utero. And there’s probably something happening in early life that imprints the autoimmune phenotype or the susceptibility to get autoimmunity. And then, obviously, there’s some trigger that occurs that happens later in life. And I would imagine that that rebooted immune system that we say the autoimmunity is gone would probably still be susceptible because you’re repopulating from a susceptible background, but maybe that trigger won’t come again.

 

I mean, one of the things people have got to realize is we’re not trying to say this is a cure in everybody who gets this treatment, it’ll only be a proportion of people, and those are the people who don’t reactivate. I mean, we need to learn a lesson is what’s triggering their reactivations if they’ve been in long-term remission. Is it an environmental agent, infection, or something like that? So I wish one knew where the autoimmunity is being triggered from, we don’t know.

 

MSDF

What sort of experiments are going on now? Is this just registries, or do you have multiple strategies? It seems like you have to do very, very long-term follow-up.

 

Dr. Giovannoni

Alemtuzumab was developed in Cambridge and they’ve been using the drug now since 1992, and they’ve got an open-label extension study that they’ve been following up, and they’ve just published a 12-year follow-up data about a month ago in the JNNP. And of that open-label study, about just over 50% of the population are stable. Then there’s obviously the clinical trial programs, and there have been relatively large phase 2 and two phase 3, and those have all gone into open-label extension and those people will be followed up indefinitely, and we’ll probably get data from that.

 

The bone marrow transplant, it’s a little bit more complicated because most of the development has been done by academic units, so there are registers. And there is a larger phase 3-type study happening in the US at the moment. The registers follow these patients up long-term, so we’ll see what happens. But the cohorts that have been treated early with the disease are doing extremely well. The majority of them, provided they get through the bone marrow transplant, their disease goes into remission and their brain atrophy rates after year 1 are within the normal range, no relapses at MRI, no new MRI activity. So it’s looking very promising.

 

The problem with bone marrow transplants, it’s quite a risky procedure. For some people it’s a risky procedure, for others it’s not, which is one of the things we find out. If you go to the community and you ask people with MS, when you say to them your chances of dying from the procedure – because in very good bone marrow transplant units now, the mortality rates are between 0.5 and 1% – a lot of people with MS will take those risks. I mean, it’s up to them, they’ve got the disease. The difficulty we have is which patients do you offer those aggressive therapies to.

 

MSDF

Does the feasibility of bone marrow transplantation go down with age?

 

Dr. Giovannoni

I mean, if you train in MS is that all these therapies really work early in the disease. I think the reason for that is the longer you’ve got MS, the more damage is left behind, and that primes that nervous system to degenerate. So when they’ve used bone marrow transplantation in secondary progressive disease and people have really got quite a lot of disability, the induction part of the chemotherapy – the chemotherapy itself is neurotoxic, so they tolerate the induction therapy very poorly. And although the bone marrow transplant switches off the inflammatory component of the MS, that damaged central nervous system is still there and they continue to progress. We think they may progress at a slower rate, we don’t know that, so it doesn’t really stop the secondary progressive phase of the disease when it’s been used in that, which is why most people who do bone marrow transplant now are shifting towards early MS when there’s much more to protect.

 

And the other issue is there’s a big theory evolving in the MS field that a part of the progressive phase of the illness is premature aging. I’m not talking about premature aging across the whole body, but premature aging within the central nervous system. We know now that any inflammatory or chronic inflammation triggers aging pathways, and that may just drive some part of the progressive component to the disease. And if that’s the case, then we’re not going to be able to modify with anti-inflammatory therapies the strategies that target aging.

 

MSDF

Is this total bone marrow ablation as you would do in any other transplant for curative purposes in oncology, or is it something less than that?

 

Dr. Giovannoni

Well, it depends who you speak to. I went into detail with this in terms of wanting to set up a bone marrow transplant program here about 15 years ago, and I opted out because the risks then were too high. So some people say you really need myeloablative therapy and some people say you don’t need as much as myeloablative; less, you know, these partially ablative ones. So there’s two schools of thought; some want to go for the aggressive and some go for the less aggressive. The Canadian group have used really aggressive induction therapy with myeloablative therapy, and they had, unfortunately, one death and some serious toxicity. So there again is a tradeoff between which one you go for, and I think the results will show over time.

 

To be honest with you, now that we’ve got alemtuzumab which is a licensed therapy, it’s going to be hard to justify using bone marrow transplant when we’ve got a less toxic monoclonal antibody available. It’s also got safety issues, but I think those safety issues are manageable with monitoring. So I think it’s going to be very hard in the current climate to justify bone marrow transplantation when you have alemtuzumab as a licensed drug.

 

MSDF

Is chemotherapy in itself a reasonable treatment?

 

Dr. Giovannoni

They’ve been tried in the past. I mean, the mistakes we made would say cyclophosphamide, which is an alkylating agent, is that when the trials were done we did them in an era when we didn’t know how to do MS trials. So they were done prior to MRI monitoring, they tended to be doing advanced MS, and the trials were underpowered. I think if we had to do cyclophosphamide in the modern era, we would have done the trials differently, and I’m almost certain they would be effective. We have mitoxantrone which is a chemotherapy agent; that’s got a license in quite a few countries. It’s unfortunately a topoisomerase inhibitor and it’s associated with translocations and causes leukemia. And that’s pretty common actually. The registries that have been tracking are reporting the incidence of mitoxantrone-related leukemia at about 1:150 to 1:200, and I think that itself takes that drug out of practice, to be honest with you. And it also is dose-related treatment; you can only give it for a certain number of infusions because it causes a cardiomyopathy, and it’s also linked to premature ovarian failure. There’s a lot of the issues about using that drug in clinical practice, and most centers now have stopped using mitoxantrone.

 

MSDF

Does this lead into the idea of aborting MS so you don’t get into a progressive phase, all these strategies?

 

Dr. Giovannoni

Yes. We all talk about secondary progressive disease. I’ve stopped using the term secondary progressive disease in isolation. I say clinically progressive disease because the progressive phase of this illness is present from the very beginning of this disease. So when people present with their very first clinical attack, a significant number then will already have had brain atrophy and cognitive impairment. And if you monitor people at every stage of the disease, there’s this progressive brain atrophy occurring. So we think the pathological substrate for progression is there from the outset.

 

What makes somebody transition into the progressive stage clinically is when the brain reserve runs out. So what stops the progressive phase manifesting is the fact that we’ve got reserve capacity and we compensate. And once that’s run out, people enter the clinically progressive phase of the disease. So I talk about progression being there from the outset; at some point in time you’ll present with secondary progressive MS, and I think it’s system-related.

 

This is one of the other concepts I’m trying to get across is that progressive disease is not just progressive disease. I mean, most people present initially with the motor system and the lower limbs or their bladder involvement, and then it gradually spreads to their arms, their cerebellar systems, etc. I call it asynchronous progressive disease, and I do this because I really want to give people with progressive MS hope that if you’ve got progression in one pathway, we may be able to treat you and prevent it from becoming clinically progressive in the other pathways.

 

So this is where we need to rethink our trials, because all of our outcome measures in clinical trials are based purely on lower limb function and mobility. If we wait for people to become progressive in that system, then use that system as a readout, we might miss an important therapy. So what we probably should do is say, well that system’s in the progressive phase, let’s focus on preventing the other systems from entering the progressive phase, those systems that have got reserve capacity. If we change our thinking like that, we’ve got a much greater chance of getting a drug licensed for progressive disease than we have at the moment.

 

MSDF

Because you can choose various endpoints to look at and show that it’s having some effect somewhere?

 

Dr. Giovannoni

Yes. The idea would be to stop or prevent people entering the progressive phase in the other systems. Once somebody’s in the clinically progressive phase in a particular neuronal system, it means that they’ve lost reserve capacity. And that reserve capacity is what predicts recovery. So somebody who is really progressing along that pathway is extremely vulnerable and probably prime to continue to progress. That’s going to be very difficult to show an effect in that pathway. And that’s what we’re doing right now. We’re saying let’s take people with progressive MS that are having walking difficulties, let’s put them in a trial and try and slow down that walking problem. And I think that’s the wrong strategy. I think we should be changing our way we do trials.

 

MSDF

My impression has been that when someone enters the secondary progressive phase, there seems to be an acceleration. But from what you say about loss of reserve leading to progression, it sounds like it’s just the same slope but without the remissions.

 

Dr. Giovannoni

Yes. We think the mechanisms are different though. There is some evidence what I call a therapeutic lag. This is complicated. Let me explain what a therapeutic lag is. When you’re in the progressive phase of the disease, we think the progression that’s occurring this year or next year has been primed by inflammation that’s occurred over the two years. So there’s a lag between the inflammatory component which damages those nerve fibers, and then they dive over the next few years. It probably damages them and they’re probably surviving and functioning but compromised, and that process then runs its course.

 

So I think what we really need to do is if we do clinical trials and switch off inflammation now, you’re not going to see an effect of an anti-inflammatory drug in the next two years, we have to look in year three, four, and five. And there is data now from extension studies supporting this. So I actually think we also need to change our trial design in progressive MS if you’re going to look at a progressing pathway; not to look in two years, we’ll be looking at year three, four, and five.

 

The current crop of trials are kind of doing that. What they’ve done is instead of having a fixed time point of two years, most of them are event-driven, so when they have enough events they will stop the trial. And the event-driven trials looks like they’re taking the follow-up into year three and sometimes year four. So we may get enough power to see if that works in the current crop of trials in progressive MS. But I really do think that we need to go to probably five years in progressive MS trials to get a readout that we can trust, based on our understanding of the progression of the disease.

 

MSDF

So can you enumerate or summarize what you think trials should look like? What one would choose as endpoints, definitions, anything else that would be different from how they’re doing it today?

 

Dr. Giovannoni

Yes. So if we’re going to continue to use the gold standard, which is EDSS, this expanded disability status goal which has a lot of psychometric problems – it’s got a flawed seeding effect, it’s not linear, it’s got a high inter-rater. . – with all those problems, we’ve still got this damn gold standard, EDSS. If we’re going to use the EDSS and we’re going to focus on mobility, then we’re going to have to do 5-year trials. And know that there’s a therapeutic lag, forget about expecting to see a result in year two and look at year three, four, and five. In addition to that, I think we need to actually then develop new outcome measures that assesses the systems that aren’t affected, like upper limb function, cognition, cerebellar, eye movements, etc., and look for differences in those systems on active treatment versus placebo. We’ve changed the question. In other words, we’re trying to prevent those systems from being damaged relative to the system that is damaged. And I think then we may get an answer. And I’m almost certain anti-inflammatory strategies that I’ve been told not to work in progressive MS will work.

 

MSDF

If you look long enough.

 

Dr. Giovannoni

If we look long enough or we change the way we define the outcomes. Because I do think that those other systems that aren’t progressing clinically will be more responsive in a shorter period of time; they’ve still got reserve capacity. And that reserve capacity really predicts recovery. We’ve seen this now in early MS is if somebody has got a low disability score and you treat them with a powerful anti-inflammatory, be it natalizumab or alemtuzumab, a significant number – 30 to 40% - actually improve in function. And that’s because they’ve got reserve capacity; they have the ability to recover function. I think if you can choose pathways that have got reserve capacity and you treat with anti-inflammatories, those pathways may have an ability to recover or improve, and you’ll see the difference between the treatments much earlier. It’s just an observation that needs to be taken into clinical trials.

 

MSDF

Locking the barn door while the horse is still in.

 

Dr. Giovannoni

Yes. This is like any other disease. There’s no point in treating a disease after you’ve missed the boat. If you speak to rheumatologists or nephrologists, it’s much better to protect the kidney and the joints before they’re damaged. The same concept needs to come into the MS field. You need to target the organ before it’s damaged, because prevention is much better than trying to promote recovery.

 

MSDF

Very good. We appreciate it. Thank you.

 

[transition music]

 

MSDF

Thank you for listening to Episode Twelve of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

[outro music]

 

 

[intro music]

 

Host – Dan Keller

Hello, and welcome to Episode Eleven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with Dr. Jack Antel about remyelination and microglia. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

Our latest data visualization reveals a mystery in relapsing-remitting MS. It appears that the annualized relapse rates of patients in the placebo arms of clinical trials – the placebo arms – have been decreasing since 1993. What could possibly account for this? We invite your hypotheses. Visit the MSDF website and go to our data visualizations page under “research resources.” From there you can connect to a discussion forum we’re hosting to share your opinions.

 

Deep brain stimulation is an extreme brain surgery that can lead to dramatic improvements in patients with Parkinson’s disease or obsessive-compulsive disorder. But in MS patients with tremor, the risk-benefit ratio varies a great deal from patient to patient. The surgery involves placing an electrode into the thalamus and stimulating the surrounding neurons to reduce tremor. However, no one is sure why the procedure works in some people with MS tremor and not in others. Last week, we published a news synthesis—including a dramatic video—on the efficacy of this surgery to treat the otherwise untreatable tremor in some MS patients.

 

We also reported on results from the phase 1 clinical trial of an anti-LINGO-1 remyelination agent. The drug, called BIIB033, is produced by Biogen Idec and proved safe and tolerable in healthy individuals and people with MS. In mouse models, the drug is shown to work by blocking LINGO-1. LINGO-1 prevents oligodendrocyte progenitor cells from differentiating into myelin-producing cells. The company is now conducting a phase 2 study to determine proper dosage in patients with MS.

 

[transition music]

 

Now to the interview. Dr. Jack Antel is a neurologist at the Montreal Neurological Institute and Hospital. His team studies remyelination and repair. He spoke with MSDF about how microglia and progenitor cells affect this process.

 

Interviewer – Dan Keller

Welcome, Dr. Antel.

 

Interviewee – Jack Antel

Thank you very much.

 

MSDF

Where do things stand now? What is the thinking of remyelination? Is it a dynamic process? Is it something that happens all at once? Is there a balance between injury and repair?

 

Dr. Antel

From the perspective of multiple sclerosis itself, we look to our pathologists who've examined the actual MS tissue, and they have established criteria by which they identify that remyelination has occurred, and thus this has been a major incentive to see whether one can accelerate that process. One can now somewhat question the certainty that we are distinguishing between actual remyelination and perhaps partial injury of myelin, and maybe part of what we've seen is actual injury rather than actual repair. The other side of the coin is from the experimental biologist who clearly have shown remyelination to occur and have identified progenitor cells as being the basis of remyelination in animal models. Now we have to bring the observation from the clinical pathology in humans together with those observations are we still certain that all of remyelination is dependent on new cells, or can previously myelinating cells still contribute. And in the context of the human disease, the issue is what is the total potential of the cells? Why doesn't everybody remyelinate? This is because there's intrinsic differences in the myelin cells that humans have. Could the myelin cells themselves be subject to injury? And also, the complicating feature is how much injury is there? So that, if the axons have been damaged, maybe they are not receptive to remyelination. And also, the chronic changes in the environment of all the other glial cells and their products in the human situation, which is after all a disease of months and years not of days and weeks, maybe this is an important influence as to why remyelination occurs or doesn't.

 

MSDF

You had mentioned partial myelination or demyelination. When one looks at a path slide, is it possible to tell whether it's going up or down? Can you distinguish one from the other?

 

Dr. Antel

So that active injury of myelin can be identified because in the active MS lesion myelin debris is freed up and picked up by the phagocytic cells – either the microglia or macrophages – so one can see that there is active injury. If one looks just at the myelin sheath itself, the criteria for remyelination is these sheaths have become rather thinned out, and the segment of the myelin sheath is shorter than in the naturally myelinated cell condition. The issue becomes whether are we absolutely sure that this is remyelination, or could one model developing this histologic feature in some way by injury? And I think that would be a very good challenge for the experimentalists to see if they can get an injury model that reproduces some myelin injury without actually killing the myelinating cells.

 

MSDF

Besides being a target for the immune response, how do glia participate in the immune response?

 

Dr. Antel

So the glia – we can refer both to the astrocytes and microglia – and as you mentioned one of the important issues I think with these cells is how they talk to the immune cells that are coming from the outside into the brain and modulating their properties. In addition, these glial cells themselves can influence the myelination process in several ways. One is that they can produce some of the same molecules that the immune cells produce or novel molecules that can either promote or directly inhibit the capacity of myelinating cells to function – so direct signaling effects on the myelinating cells. The other is they are producing molecules that change the environment so that processes either grow out or don't grow out from the myelinating cells. So we have to consider the glia, which are very dynamic and thus become a target for therapeutic manipulation, in terms of both their effects on immune cells but also can they be so, if you will, "good guys" or "bad guys" in terms of the promoting the myelination process.

 

MSDF

We think of some of the present drugs as modulating the immune system and trafficking and its effect on effector cells. But do you think that some of these may be affecting bystander cells, or I suppose maybe they're not bystanders if they're actively involved. Could they have an affect on glia?

 

Dr. Antel

I think that this is an emerging opportunity in the field because we are now having the first generation of drugs that actually access the central nervous system. The initial generation of drugs, many of the monoclonal antibodies, we felt were acting outside of the nervous system – either on immune cells themselves or on the cells that comprised the blood-brain barrier but with some particularly of the small molecule drugs that access the central nervus system – that these drugs have the capacity to interact with the neural cells. If we use as an example the family of agents that we refer to as this sphingosine-1-phosphate receptor modulators, S1P agents, there has long been data that these receptors are expressed on all cells, including all of the neural cells, and there is existing data that S1P modulators can affect the function of glial cells. Now how this translates into effects that are clinically relevant is the challenge that's ongoing now.

 

MSDF

How does all of this relate to progressive MS?

 

Dr. Antel

So progressive MS, I believe, is an entity that we have not totally understood yet, and we have to consider it in its parts, namely is progressive MS reflective of ongoing injury to the myelinating cells or the underlying axons? Is this a reflection of the injured cells no longer able to maintain themselves are they metabolically failing? And that can we distinguish these processes because if it's ongoing immune injury – whether related to the adaptive or innate immune system – then it makes sense to target those process. If it's an injury or metabolic failure, then that would be another approach. I think we have to consider whether progressive MS, again has evolved over many, many years, and whether one of our challenges is reducing the initial injury process can avoid many of these long-term events.

 

MSDF

In secondary progressive MS, do you see that there's sort of a tipping point? Is there something different in secondary progressive once that occurs?

 

Dr. Antel

It's difficult to provide an answer, and I think here is an area particularly where careful clinical studies are guiding us that the initial notion that multiple events triggered a later process would have been a very nice system to have because then stopping a process early would have predicted a beneficial later response. We are struck that the clinical data is suggesting that progression can occur perhaps even in the absence of ongoing inflammation whether the two are dissociated, at least in some cases, is a real concern. And thus, just controlling the initial immune response – because it triggers a later event – may not be sufficient. And the reverse, which I think has received perhaps less attention, is that from the clinical perspective multiple people have multiple disabling acute events and do not develop the progressive process. So it is not clear that the two are absolutely linked; whether there are genetic susceptibility factors that determine this have not yet emerged; whether it's the nature of the injury; or whether we have multiple diseases processes.

 

MSDF

We often think of bench-to-bedside as the pathway for advancements. Now you had told me earlier that you're working with people in the opposite direction; you're finding things in the human condition and then leading to laboratory validation. Can you tell me a little bit about that?

 

Dr. Antel

I think this is a very important aspect and why it is important that the clinical and clinical pathology experts really identify the core issues so that they can be taken to a laboratory and experimentally addressed. That in MS, we're dealing with a disease that develops over months and years making it more difficult to model it precisely. It's a disease where we have not established the initiating event. Whereas in the animal system, we usually use a arbitrary antigen if we were going to model an immune mediated disorder. We model the demyelination/remyelination process usually by acute toxins in the animal systems; whereas this is not the case in MS that specific exposure. And so I think we need to continue to develop our model systems that can induce some type of progressive disorder that is not specifically introduced perhaps by a specific antigen, at least the antigens we use currently.

 

MSDF

Knowing that remyelination is possible, is there an implication that it may be going on in all of us in healthy brain at all times where you actually get turnover? And if so, can you capitalize on this kind of system?

 

Dr. Antel

So the issue of turnover of myelin, I think, has not been emphasized sufficiently until recently both from the perspective if we have continuous turnover whether this may be one of the mechanisms whereby antigens are presented to the immune system. The other in terms of the turnover rate of myelin or oligodendrocytes – whether the health of these cells is damaged by the disease process, and whether a limiting factor over time is that the injury of the cells, which could be quite subtle – so that the cells are not killed, but they've impaired their function either to maintain the interaction with axons or the necessary transport of key molecules down the processes. Whether interruption of this then results in the inability of the cells to maintain their myelination properties and to continue the turnover or what might be a repair activity. And we interpret this as a later progression of the disease.

 

MSDF

On the topics we've been discussing, is there anything important to add?

 

Dr. Antel

I think the importance is that we now are turning our attention to these topics. That it is very timely that we do this – because until we could control the actual disease activity through immunomodulatory therapies – if that aspect was not controlled it would be much more difficult to think of trying to control the overall disease process. And also, as we couple the biology with careful clinical observations and the advances in imaging of the human brain, so that it gives us greater opportunities to bring our theories from the lab to the clinics and see whether we really impact in a positive way on the processes we've been discussing.

 

MSDF

Very good. We appreciate it.

 

Dr. Antel

My pleasure.

 

[transition music]

 

MSDF

Thank you for listening to Episode Eleven of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie [intro music]

 

 

Host – Dan Keller

Hello, and welcome to Episode Eleven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with Dr. Jack Antel about remyelination and microglia. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

Our latest data visualization reveals a mystery in relapsing-remitting MS. It appears that the annualized relapse rates of patients in the placebo arms of clinical trials – the placebo arms – have been decreasing since 1993. What could possibly account for this? We invite your hypotheses. Visit the MSDF website and go to our data visualizations page under “research resources.” From there you can connect to a discussion forum we’re hosting to share your opinions.

 

Deep brain stimulation is an extreme brain surgery that can lead to dramatic improvements in patients with Parkinson’s disease or obsessive-compulsive disorder. But in MS patients with tremor, the risk-benefit ratio varies a great deal from patient to patient. The surgery involves placing an electrode into the thalamus and stimulating the surrounding neurons to reduce tremor. However, no one is sure why the procedure works in some people with MS tremor and not in others. Last week, we published a news synthesis—including a dramatic video—on the efficacy of this surgery to treat the otherwise untreatable tremor in some MS patients.

 

We also reported on results from the phase 1 clinical trial of an anti-LINGO-1 remyelination agent. The drug, called BIIB033, is produced by Biogen Idec and proved safe and tolerable in healthy individuals and people with MS. In mouse models, the drug is shown to work by blocking LINGO-1. LINGO-1 prevents oligodendrocyte progenitor cells from differentiating into myelin-producing cells. The company is now conducting a phase 2 study to determine proper dosage in patients with MS.

 

[transition music]

 

Now to the interview. Dr. Jack Antel is a neurologist at the Montreal Neurological Institute and Hospital. His team studies remyelination and repair. He spoke with MSDF about how microglia and progenitor cells affect this process.

 

Interviewer – Dan Keller

Welcome, Dr. Antel.

 

Interviewee – Jack Antel

Thank you very much.

 

MSDF

Where do things stand now? What is the thinking of remyelination? Is it a dynamic process? Is it something that happens all at once? Is there a balance between injury and repair?

 

Dr. Antel

From the perspective of multiple sclerosis itself, we look to our pathologists who've examined the actual MS tissue, and they have established criteria by which they identify that remyelination has occurred, and thus this has been a major incentive to see whether one can accelerate that process. One can now somewhat question the certainty that we are distinguishing between actual remyelination and perhaps partial injury of myelin, and maybe part of what we've seen is actual injury rather than actual repair. The other side of the coin is from the experimental biologist who clearly have shown remyelination to occur and have identified progenitor cells as being the basis of remyelination in animal models. Now we have to bring the observation from the clinical pathology in humans together with those observations are we still certain that all of remyelination is dependent on new cells, or can previously myelinating cells still contribute. And in the context of the human disease, the issue is what is the total potential of the cells? Why doesn't everybody remyelinate? This is because there's intrinsic differences in the myelin cells that humans have. Could the myelin cells themselves be subject to injury? And also, the complicating feature is how much injury is there? So that, if the axons have been damaged, maybe they are not receptive to remyelination. And also, the chronic changes in the environment of all the other glial cells and their products in the human situation, which is after all a disease of months and years not of days and weeks, maybe this is an important influence as to why remyelination occurs or doesn't.

 

MSDF

You had mentioned partial myelination or demyelination. When one looks at a path slide, is it possible to tell whether it's going up or down? Can you distinguish one from the other?

 

Dr. Antel

So that active injury of myelin can be identified because in the active MS lesion myelin debris is freed up and picked up by the phagocytic cells – either the microglia or macrophages – so one can see that there is active injury. If one looks just at the myelin sheath itself, the criteria for remyelination is these sheaths have become rather thinned out, and the segment of the myelin sheath is shorter than in the naturally myelinated cell condition. The issue becomes whether are we absolutely sure that this is remyelination, or could one model developing this histologic feature in some way by injury? And I think that would be a very good challenge for the experimentalists to see if they can get an injury model that reproduces some myelin injury without actually killing the myelinating cells.

 

MSDF

Besides being a target for the immune response, how do glia participate in the immune response?

 

Dr. Antel

So the glia – we can refer both to the astrocytes and microglia – and as you mentioned one of the important issues I think with these cells is how they talk to the immune cells that are coming from the outside into the brain and modulating their properties. In addition, these glial cells themselves can influence the myelination process in several ways. One is that they can produce some of the same molecules that the immune cells produce or novel molecules that can either promote or directly inhibit the capacity of myelinating cells to function – so direct signaling effects on the myelinating cells. The other is they are producing molecules that change the environment so that processes either grow out or don't grow out from the myelinating cells. So we have to consider the glia, which are very dynamic and thus become a target for therapeutic manipulation, in terms of both their effects on immune cells but also can they be so, if you will, "good guys" or "bad guys" in terms of the promoting the myelination process.

 

MSDF

We think of some of the present drugs as modulating the immune system and trafficking and its effect on effector cells. But do you think that some of these may be affecting bystander cells, or I suppose maybe they're not bystanders if they're actively involved. Could they have an affect on glia?

 

Dr. Antel

I think that this is an emerging opportunity in the field because we are now having the first generation of drugs that actually access the central nervous system. The initial generation of drugs, many of the monoclonal antibodies, we felt were acting outside of the nervous system – either on immune cells themselves or on the cells that comprised the blood-brain barrier but with some particularly of the small molecule drugs that access the central nervus system – that these drugs have the capacity to interact with the neural cells. If we use as an example the family of agents that we refer to as this sphingosine-1-phosphate receptor modulators, S1P agents, there has long been data that these receptors are expressed on all cells, including all of the neural cells, and there is existing data that S1P modulators can affect the function of glial cells. Now how this translates into effects that are clinically relevant is the challenge that's ongoing now.

 

MSDF

How does all of this relate to progressive MS?

 

Dr. Antel

So progressive MS, I believe, is an entity that we have not totally understood yet, and we have to consider it in its parts, namely is progressive MS reflective of ongoing injury to the myelinating cells or the underlying axons? Is this a reflection of the injured cells no longer able to maintain themselves are they metabolically failing? And that can we distinguish these processes because if it's ongoing immune injury – whether related to the adaptive or innate immune system – then it makes sense to target those process. If it's an injury or metabolic failure, then that would be another approach. I think we have to consider whether progressive MS, again has evolved over many, many years, and whether one of our challenges is reducing the initial injury process can avoid many of these long-term events.

 

MSDF

In secondary progressive MS, do you see that there's sort of a tipping point? Is there something different in secondary progressive once that occurs?

 

Dr. Antel

It's difficult to provide an answer, and I think here is an area particularly where careful clinical studies are guiding us that the initial notion that multiple events triggered a later process would have been a very nice system to have because then stopping a process early would have predicted a beneficial later response. We are struck that the clinical data is suggesting that progression can occur perhaps even in the absence of ongoing inflammation whether the two are dissociated, at least in some cases, is a real concern. And thus, just controlling the initial immune response – because it triggers a later event – may not be sufficient. And the reverse, which I think has received perhaps less attention, is that from the clinical perspective multiple people have multiple disabling acute events and do not develop the progressive process. So it is not clear that the two are absolutely linked; whether there are genetic susceptibility factors that determine this have not yet emerged; whether it's the nature of the injury; or whether we have multiple diseases processes.

 

MSDF

We often think of bench-to-bedside as the pathway for advancements. Now you had told me earlier that you're working with people in the opposite direction; you're finding things in the human condition and then leading to laboratory validation. Can you tell me a little bit about that?

 

Dr. Antel

I think this is a very important aspect and why it is important that the clinical and clinical pathology experts really identify the core issues so that they can be taken to a laboratory and experimentally addressed. That in MS, we're dealing with a disease that develops over months and years making it more difficult to model it precisely. It's a disease where we have not established the initiating event. Whereas in the animal system, we usually use a arbitrary antigen if we were going to model an immune mediated disorder. We model the demyelination/remyelination process usually by acute toxins in the animal systems; whereas this is not the case in MS that specific exposure. And so I think we need to continue to develop our model systems that can induce some type of progressive disorder that is not specifically introduced perhaps by a specific antigen, at least the antigens we use currently.

 

MSDF

Knowing that remyelination is possible, is there an implication that it may be going on in all of us in healthy brain at all times where you actually get turnover? And if so, can you capitalize on this kind of system?

 

Dr. Antel

So the issue of turnover of myelin, I think, has not been emphasized sufficiently until recently both from the perspective if we have continuous turnover whether this may be one of the mechanisms whereby antigens are presented to the immune system. The other in terms of the turnover rate of myelin or oligodendrocytes – whether the health of these cells is damaged by the disease process, and whether a limiting factor over time is that the injury of the cells, which could be quite subtle – so that the cells are not killed, but they've impaired their function either to maintain the interaction with axons or the necessary transport of key molecules down the processes. Whether interruption of this then results in the inability of the cells to maintain their myelination properties and to continue the turnover or what might be a repair activity. And we interpret this as a later progression of the disease.

 

MSDF

On the topics we've been discussing, is there anything important to add?

 

Dr. Antel

I think the importance is that we now are turning our attention to these topics. That it is very timely that we do this – because until we could control the actual disease activity through immunomodulatory therapies – if that aspect was not controlled it would be much more difficult to think of trying to control the overall disease process. And also, as we couple the biology with careful clinical observations and the advances in imaging of the human brain, so that it gives us greater opportunities to bring our theories from the lab to the clinics and see whether we really impact in a positive way on the processes we've been discussing.

 

MSDF

Very good. We appreciate it.

 

Dr. Antel

My pleasure.

 

[transition music]

 

MSDF

Thank you for listening to Episode Eleven of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

[outro music]

 

 

Schmidt is vice president of scientific operations.

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

[outro music]

 

 

[intro music]

 

Host – Dan Keller 

Hello, and welcome to Episode Ten of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with Dr. Richard Ransohoff about his group’s latest research. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

We reported on two research articles on B cells published in “Science Translational Medicine". The authors suggested B cells are activated in the peripheral lymph nodes before migrating to the CNS in patients with MS. It appears that after activation the B cells travel back and forth between the CNS and the lymph nodes. The findings have implications for monoclonal antibodies rituximab and ocrelizumab, which reduce peripheral B cell numbers, as well as natalizumab, which prevents lymphocyte migration across the blood-brain barrier. 

 

Together, MSDF and our non-profit publisher, the Accelerated Cure Project – ACP – are committed to speeding the pathway toward a cure for MS. Among the news and resources we provide is a list of more than two dozen tissue repositories, including ACPs. Visit our website and click on the “tissue repositories” button under the “research resources” tab to browse through repositories from all over the globe.

 

Another part of our goal in working faster toward a cure is to provide a place where researchers can share their experiences and expertise with one another and also debate controversial issues in MS research. We encourage researchers and clinicians from all disciplines to log onto our forum and discuss their latest research, techniques, and discoveries. We also encourage you to help keep us up-to-date on your latest work by e-mailing us directly. Send information you’d like to share on job postings, meetings, funding opportunities, or other news to editor@msdiscovery.org.

 

[transition music]

 

Now to the interview. Dr. Richard Ransohoff is the director of the Neuroinflammation Research Center at the Cleveland Clinic and a member of the MSDF scientific advisory board. His research group focuses on chemokines and chemokine receptors. He met with our senior science writer, Carol Morton, to discuss his latest findings.

 

Interviewee – Richard Ransohoff

Glad to be here with you today, Carol. The paper that we just published is the result of at least five year's of work. The fundamental question that we tried to answer in this paper I guess if we take a step back and say one looks at an active MS lesion, and one sees a tremendous infiltrate of macrophages, which are clearly involved in the removal of myelin, which is the fundamental problem in MS. And because of the fact that these macrophages have two sources – meaning that some of them come from microglia that are resident within the brain and are macrophage like; and others are differentiated from blood monocytes that have infiltrated the tissue – it's worth wondering whether all the macrophages that look identical by their size and appearance and tissue staining are also functionally identical. And in the case of an MS like disease, by functionally identical, what we mean is are some of these cells that live in the tissue or in the lesion are some of them good guys and others are bad guys, or are they all uniformly bad guys? The reason it's worth asking that question – beyond simple curiosity – is that if you can figure out who are the good guys and the bad guys the treatment approaches become much clearer to you. So for example, if the infiltrating monocytes are the bad guys, then it's possible to apply certain kinds of medications simply to keep them out of the lesion, keep them in the bloodstream. And we already have medicines that we use in MS that take that sort of general approach. So medicines like natalizumab, which blocks cells from leaving the bloodstream and going into tissue, is one. A medicine like fingolimod, which locks up some cells in the lymph nodes and also may stabilize the blood-brain barrier, is another. And a medicine like alemtuzumab that simply removes a large fraction of the cells in the bloodstream that could participate in the tissue damage is a third. So we do know how to treat the blood cells in the way that I'm describing. Most of that work is focused on lymphocytes, not monocytes. But it could certainly be refocused. On the other hand, if the microglia are the bad guys, then the approach becomes completely different, and it's important then to figure out what sort of molecular cues are the microglia responding to and how can we block that part of the MS disease process. 

 

Interviewer – Carol Morton

Because the microglia already are in the brain. So the existing medicines have to do with peripheral immune cells that are coming into the brain during disease, right?

 

Dr. Ransohoff

Correct. It would be important, then, to get the medicine in the brain. And when you take that approach, you have to really be very careful that the medicine doesn't have adverse effects on other brain cells. So we started from position that there were no existing markers to identify these cells in the tissue. And we were lucky enough to find out that recently developed genetic models, which tagged different myeloid cells with different fluorochromes could be used to discriminate between the monocyte derived macrophages and the microglia derived macrophages right at the onset of EAE. It turned out that we could first ask which of the two cell types contained myelin debris at the onset of EAE. That seemed like the simplest way to go after our question because we really wanted to know which cell was damaging and taking up myelin. And it turned out that both cell types had myelin in them, and so that really didn't answer the question for us. And if we gave it another moment's thought, we realized that some cells could be damaging myelin, and other cells could be removing debris. And we know that debris removal is part of the repair process. So we had to think of another way to address the problem. And through a relatively long process of developing different techniques, we figured out a way to adapt the data from studying conventional fluorescence confocal microscopy images of the cells and the tissue so that we could identify the same cells in EM sections. Because we had to go to the EM level really to answer the question that we were going after. And we used a new instrument at the Cleveland Clinic, which is one of only a few of this type of instrument at the time around the world, and it allows you to construct a 3D EM picture of certain tissue elements. And so, we set about doing that, and we identified the monocytes in the tissue and the microglia in the tissue using that approach, and we also pointed out how these two cell types were interacting with what you call the axoglial unit, which is the myelin wrap around the axons in the white matter of the spinal cord of the mouse. And we did quite a few samples from quite a few mice. And the answer to our question was very clear. Just to make it simple, the monocytes were the bad guys – they were attacking myelin and removing it from axons even when the axons appeared perfectly healthy and normal, and the myelin appeared normal where it wasn't being pulled off by the monocytes. And the microglia seemed a little bit later to begin to remove the debris. And the answer was pretty unambiguous; we never found microglia attacking myelin directly. And there was a very satisfying resolution to something that had been bothering us for a long time. We also got extra bits of information beyond what we were looking for. We found that the monocytes seemed to attack the axoglial unit not at random but at only selected places, and it seemed as though they focused primarily on the nodes of Ranvier. And it seemed as though that complicated structure was particularly vulnerable to attack. We think that that's because these structures – being as complicated and delicate as they are – become somewhat disrupted in the inflammatory environment, and the monocytes recognize something and take out after it. So we're now very intent on figuring out what the molecular signals are that attract the monocytes. We think that'll be important to know. At the same time, we thought it was important to figure out whether the gene expression in the monocytes and microglia reflected the different behaviors that we saw. And we found that the gene expression profiles in the monocytes and microglia were extremely different. The monocyte profile was almost exactly what you would predict if you watched their bad behavior and that was one of increasing many, many genes associated with inflammatory signaling, production of inflammatory mediators, and most importantly phagocytosis. The microglia, by contrast, showed a lot of downregulation of genes that are expressed in microglia from the healthy brain. So the microglia seemed to be repressed from doing things that they do in the healthy brain, and their metabolism seemed to be in a sense shutoff. They showed an inhibition of the ability to express genes by making RNA to maintain cytoplasmic and cytoskeletal organization to carryout phagocytosis and to make inflammatory mediators. So the microglia seem very repressed by comparison to microglia from the healthy brain. And so, our followup plans for the microglial side of things is to understand whether that phenotype persists for very long because the microglia need to be quite active in the process of repair and make a contribution to that process. And if their metabolism is sort of slowed down and stunted, they may have troubles to do that. So we believe the way they ask they question is to do not only additional gene expression studies but epigenetic studies, as well. And the epigenetic question we're asking is whether DNA methylation, which will turn off gene expression quite efficiently and in a long-lasting way, is changing as the microglia go from healthy brain to EAE onset and finally to recovery. We have some strong preliminary data that the gene expression decreases that we've already seen are associated with DNA methylation changes so they may be quite long-lasting. And we want to follow it through until the mice begin to recover and remyelinate to see whether the microglia recover their ability to contribute to repair. The reason we think that question is crucially important is because if this is characteristic of what happens in multiple sclerosis there may be ways to intervene such that the amount of damage is limited – we already do that pretty well – but also so the amount of repair is maximized. And I'm not certain that we understand how to do that as well as we would like. 

 

MSDF

You're calling them both macrophages. Is that a certain state of activation?

 

Dr. Ransohoff

So when I say macrophage, it's a kind of a shorthand term for a relatively activated form of a mononuclear phagocyte in a tissue doesn't tell you where it came from – doesn't tell you if it came from a monocyte or a tissue macrophage or some other source – it just tells you what its lineage is, it's a mononuclear phagocyte, and that it's in a tissue and is displaying signs of activation. 

 

MSDF

I understand that the difference in the identity between the microglia and the macrophage has been a long-standing problem, and it sounds like you leapfrogged ahead of that to look at the functional difference. So is your study the last word on that? Is there other evidence that reinforces it, or I don't want to say contradicts but…

 

Dr. Ransohoff

Are there other ways of looking at it?

 

MSDF 

…or unresolved issues that it raises, like new questions that it raises. And I'm curious about the implications for thinking about that in mice and then the implications in people with MS.

 

Dr. Ransohoff

It's always important to be mindful of the limitations of one's research approach. So we try to do that. The approach that we took had a bunch of technical reasons. Our fundamental question was are monocytes and microglia different in EAE tissues? In order to ask that and in order to ask it in a sort of a meaningful and balanced way, we chose the moment of onset of the EAE. And the reason was, first of all, that we thought the most important elements of damage to the myelin were taking place at that moment. So we wanted to know how did the disease get started. And secondly, because the preliminary work that we did showed that the monocytes and microglial cells were present in those lesions absolutely gathered together in a small space, densely intermixed with each other, and in equal numbers. So we weren't biasing the case against one cell or the other; there were equal numbers of both, and they were in the same time and place. So that's a good rationale. At a technical level, the labeling that we were using is most efficient at that moment. And so, there were lots of reasons to do it that way. That tells you a good deal about what's going on at that moment; it doesn't tell you what the fate of the monocyte derived cells is. And it doesn't tell you very much about the function of the microglia. The reason that the microglial function is a open question and an important one is because two groups – one about 10 years ago, Frank Heppner and Adriano Aguzzi and others; and then more recently Marco Prinz and his colleagues – published very strong evidence that microglia play some undefined, important role in EAE. Prinz's work is, I think, the most direct and convincing. He used a way to delete a particular inflammatory gene from microglia, and he showed that in mice where the microglia lack this inflammatory – it's a major contributor to inflammatory signaling, called TAC1 – those mice are almost resistant to EAE. And so, if you put his work together with ours, you really have a fascinating, open question. And that is okay, if the microglia at the onset of EAE look very repressed and nonfunctional, but the microglial inflammatory response is necessary for EAE to occur, then it suggests that before the onset – at some early time point – there is something the microglia are doing that makes the tissue able to support the EAE process. And so, we're going to go after that; we want to understand that to some extent. And it also, as I said, it leaves open what are the microglia doing in the process of repair, which we think is very important. So I think it is always the case that new bits of research open up new questions. We hope that we've opened up good and answerable questions. 

 

MSDF 

Great. Well, thank you. This is…I appreciate you taking the time to do this. So is there anything else that I should be asking about this study or more broadly that you wanted to emphasize…add or emphasize?

 

Dr. Ransohoff

The only thing I want to add is that this is a particularly exciting time for this type of research. It's a time when all the work we've done over the years in MS begins to pay off not just for people with MS but also for people with other types of brain disease. I think that the people who have studied MS over the years have a unique contribution to make to understanding diseases that we worry about like Alzheimer’s disease. And vice versa people that study Alzheimer’s disease and other sorts of degenerations can make a contribution understanding MS. So it's a kind of coming together of these two different types of research.

 

MSDF

Can you elaborate a little bit more? Is that because more of the basic science is understood, and people can apply it in these different disease contexts? 

 

Dr. Ransohoff

I think it's a combination of things. One is that people with a background studying MS have spent their lives working on inflammation, and a good deal has been learned. The thing that makes that now applicable to other conditions is that it is becoming clear that every time there's any sort of injury to the brain there will be a reaction. And elements of that reaction will resemble what you call inflammation, and that will lead to either repair process or further damage depending on the nature of the disease and other factors that we don't know about. Those of us who have worked on MS can make a contribution to that research enterprise by sharing what we know about inflammation. As I say, it's a time which is exciting, and I think we'll be productive.

 

MSDF 

You're so good at explaining all of this. Thank you so much.

 

Dr. Ransohoff

Oh, thank you. 

 

[transition music]

 

Thank you for listening to Episode Ten of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations. 

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

[outro music] 

 

[intro music]

 

Host – Dan Keller

Hello, and welcome to Episode Nine of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with researcher Amit Bar-Or about how children with MS can illuminate early mechanisms of the disease. But to begin, here's a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org.

 

According to a Cochrane meta-analysis, interferon-beta and glatiramer acetate are clinically similar treatments for multiple sclerosis. Researchers analyzed five head-to-head clinical trials and found that both drugs did similarly well in improving disability scores and MRI measures in patients with relapsing remitting MS. The researchers were not able to measure quality of life scores for the disease-modifying therapies.

 

We also published a Research Roundup this week all about social media and the role it plays in science. Social media can sometimes work against the scientific method if patients in a clinical trial are in the habit of oversharing on blogs, Facebook, or Twitter. Patients who discuss their symptoms online might affect the blinding of clinical trials. It’s not all bad, though. We also wrote about some great social media sites for researchers such as ResearchGate, LinkedIn, and even Reddit. We also shared some amusing links on how scientists can improve their communication skills such as the “Up-Goer Five,” a schematic of the Saturn V rocket explained using only the 1000 most commonly used words in English.

 

Every week we curate research articles on all topics related to multiple sclerosis and highlight our favorites in the “Editors' Pick.” Last week, some of our favorites were a review on oligodendrocytes, a research article about the origin and maturation of B cells, and a review about how the relationship between axons and myelin is involved in demyelination. You can see our weekly picks by going to our website, clicking on the “Papers” tab, and selecting “Editors’ Picks.” In addition to the Editors’ Picks, we link to every MS-related study found in PubMed. Last week was a banner week for MS studies. One hundred four were published, and we linked to them all.

 

[transition music]

 

Now to the interview. Dr. Amit Bar-Or is an associate professor of neurology and neurosurgery at McGill University. Some of his work focuses on multiple sclerosis in children and how they can shed light on the origin of the disease.

 

Interviewer – Dan Keller

Welcome, Dr. Bar-Or. Let's talk about pediatric MS and what we can learn from it, especially about treating children but also about what it tells us about the disease, in general. Where does it stand now? What have you found in children?

 

Interviewee – Amit Bar-Or

Well the last few years have seen a substantial increase in the appreciation that MS can occur, does occur in children. Probably one out of every twenty adults with MS will have had an initial episode clinically that manifested in the pediatric age group, which one defines somewhat arbitrarily as 18 in most places. But the presence of MS in children, of course, you can imagine creates a particularly sensitive clinical context with a lot of challenges to both the child and the family and caregivers. So understanding more about pediatric onset MS – for the purpose of better caring for the children – is one important accomplishment of some of the more recent insights that have been gained in the groups that have been studied. The other, of course, is that a challenge that we have, in general, in the MS field is understanding more about what initiates MS. What are the initiating mechanisms? We've learned a fair bit but still have more to learn about the genetics and about the environmental contributions. And we know that in adults with MS one can measure certain abnormalities, for instance, in their immune response, but we really don’t know whether an abnormality that is measured in an adult represents a consequence of dysregulation and an epiphenomena that may be abnormal but is not going to benefit the illness if you treat it, as opposed to an abnormality that is very much involved in mediating the problem. So the children given that at least, on the average, they're going to be closer to the biological onset of the illness could this provide an opportunity to get insights into earlier mechanisms in a context that is less confounded by such epiphenomena of chronicity, of long-standing illness. And so, one is viewing the studies that are ongoing now – in terms of trying to better understand the pediatric MS context – both in terms of the merits of understanding them for their own sake, as well as a potential window into the broader spectrum. One of the first questions that you then need to ask if you're considering whether children can teach you about MS, in general, is whether MS in children is the same illness as MS in adults. Maybe they're different illnesses. And so one of the approaches that has been taken is to say in adults who develop MS as adults the field has identified certain genetic risk factors and certain environmental exposures that are thought to contribute to risk. And one of the first questions that has been asked is do those same risk factors – genetic and environmental – play out in children who develop MS? And the answer is essentially yes. For the same types of genetic contributors that have been identified in adults, one can see them as risk factors for developing MS in children. And the same environmental exposures – which include, for instance, low levels of vitamin D or exposure to a particular virus called Epstein-Barr virus at a certain phase – these again in children have emerged as being risk factors for the development of MS. So one thinks that at least based on that indirect evidence we can think of pediatric onset MS as, indeed, a reflection of the same illness at earlier time points and again reinforcing the value of understanding early mechanisms less encumbered by chronic disease processes.

 

MSDF

What early mechanisms have you been able to discern from looking at the development of MS in children?

 

Dr. Bar-Or

Well, there are a few very interesting observations that have emerged, and they include observations both on the immune system side and on the central nervous system side. So I'll start with the central nervous system side. We have always been challenged with the effort of trying to understand what are the actual targets of injury in multiple sclerosis. Certainly over the years, it's been described as an illness that affects myelin – the myelin making cells or the oligodendrocytes – so people have considered myelin antigens, or potential targets, as important targets in the disease. But much of that thinking has, in fact, been shaped by the most commonly used animal model system, which is experimental autoimmune encephalomyelitis, where you, in fact, inoculate the animal in its periphery with an antigen of the CNS typically a myelin antigen such as MBP or PLP or MOG. The animal has T cells that then get activated in the periphery that can respond to that antigen. They traffic to the central nervous system, identify the antigen, and contribute to an inflammatory injury process. In MS, though, we do not know what the triggering insult is or what they are in terms of the sequence, and we still don't really know what the actual targets of the illness are. This is important because more and more we've appreciated over the last decade or two that in addition to the myelin and the oligodendrocytes there's a very important injury to the neurons and their axons – the neuronal cell bodies and their extensions where they deliver their signals – which are typically wrapped in some cases in myelin, and others remain demyelinated or lacking in myelin. The issue of what the target is could guide both a better insight into initiating mechanisms – and how to deal with them therapeutically – as well as therapies that are designed to try to target very specific immune responses. Because if we knew what the specific antigens were, we might be able to develop approaches to change the immune system in what's called an antigen-specific way. Which means we try to change only the bad guys' cells or enhance the very specific regulatory cells that will control them without impacting the rest of the immune system, which would be conceptually much better in terms of having both benefit without risks of limiting the ability of the immune system to do, for the most part, what it does normally. One study in which we had the opportunity to compare spinal fluids from children presenting with a first episode of what may or may not be MS, and these children are then followed very, very carefully prospectively – meaning forward in time – as part of the Canadian Pediatric Demyelinating Disease Study was to establish over time who, in fact, has MS and who doesn't. And then go back to those early samples from that first clinical event and compare it what's called a proteomic level where we say we don’t know what the differences might be, but let's use a technology that breaks the CSF down – the cerebrospinal fluid down – into all of the components that make the different proteins. And then we have a survey of all of the different protein content and compare between the two. And we anticipated that we would see differences in those typical myelin antigens that the community has thought over the years are the relevant targets. So first surprise was we did not see any differences in those particular previously or traditionally implicated antigens. However, we did see differences in a number of molecules that are referable to a tiny little apparatus that serves an important physiologic function, and that's called the axoglial apparatus. That area is a tiny, tiny area where the glial cell – in this case the oligodendrocyte, the myelinating cell – its membrane dives down and attaches to the axon. That point of contact is part of what forms the axoglial apparatus. And it becomes a very enticing potential target of injury because an injury to that target would be expected to cause, on one hand, injury to the myelinating cell (maybe leading to demyelination) but also could produce an injury to the axon itself perhaps contributing to the axonal and neuronal injury. And again, we now know that both of those injuries are very much part of the MS disease process, or at least part of the consequence of the MS disease process. So this is just one study in children where we may be getting clues in a more refined way to the particular early targets of the disease or those structures involved in early in the disease, which is now guiding some of the thinking about how to followup on that both to better understand and potentially target therapeutically. An example on the immune system side is that there has been the sense in the broad community in MS and in other human autoimmune conditions that certain types of cells – that are called effector cells – may be dysregulated in MS either because they are overly active or insufficiently regulated or both. So either an effector problem, a regulator problem, or a combination of the two. But it's been difficult to identify which of these cell subsets is really involved in the disease as opposed to dysregulated, as I mentioned before, as a consequence of the disease. And the children have provided an opportunity to again look early on. And one study had identified that one of the abnormalities had appeared to involve a failure of normally developing regulatory T cells – this is work by Regitta Walderman (12:20) and Betina Belint at the time – which showed very nicely that in children with MS, as compared to controls, there seems to be a deficiency in the development or the maintenance of regulatory T cells. And in fact, it looked as though cells that normally get educated by an organ that we call the thymus, which is very active particularly in children, seemed to be getting older faster in the kids with MS. And so this raises the interesting question of whether there is a premature senescence or premature aging, in a sense, of certain immune cell populations so that over time their functional capacity is not quite the same, and if this is on the regulatory cell side and you have a diminished capacity for whatever reason you might expect the effector cells to be able to spillover inappropriately and participate in disease. So those are two examples – one of the neurobiological side and one of the immunological side – where children are providing what I would consider very important insights into the overall MS spectrum.

 

MSDF

Let me ask you about the injury to the axoglial complex. Glia provide supporting roles both nutritionally and through other molecules and as well as physically. Do you think this is an injury to the oligodendrocyte – which then impacts the axon – or is it some sort of attack which just hits this area, in general?

 

Dr. Bar-Or

Well this is a great question. And there's an ongoing discussion as to the chicken/egg; what gets injured first? What we do know is that when you look at the available tissue for studying pathology of MS – which, of course, tends to be quite biased to late in the disease where people may die for other reasons and postmortem – we have relatively little insight pathologically in what's happening in patients in early stages of the disease. Fortunately, people who develop MS even through the diagnosis rarely, rarely require a biopsy to get tissue to establish the diagnosis. And in fact, if you're doing a biopsy, it's usually because it's atypical, not typical. So we have several groups who are working hard and making important contributions, including into this earlier event, but there is still a big gap in our understanding of the early events and hence the very difficult to talk about initiating processes. But you bring up the very important context of the neurobiology of MS, which involves the ongoing function and integrity of the brain cells, including the neurons and the different glial cells. Those include the oligodendrocytes which make myelin but also the astrocytes which provide, among other things, important support to the blood-brain barrier and important support to the neurons, as well as the microglial cells which are very crafty cells of the central nervous system that probably performs several different functions. And all of these cells when they get activated or insulted they may fail to provide the normal physiologic protection, or they may even actively contribute to propagating injury. If you injure the oligodendrocyte in the myelin, the axon that is served by that myelin is working harder and may peter out over time. On the other hand, the integrity of the axon is important for the oligodendrocyte to maintain its myelination and its wrapping (15:34). So there's very important crosstalk, and it is very likely that injuring one element sufficiently will result in deterioration of the other regardless of which one you're injuring first. From a therapeutic standpoint, our efforts are to understand this crosstalk better and to understand how to try to establish protection, if not repair, of any one of these elements as part of the overview. It's clear that if you don't have an axon there's nothing to myelinate; if you don't have the myelinating cells you're left with bare axons that don't function or survival as well with the increased demand. And so, we need to have a more complete view so that we can approach not just a single biology at a time but, of course, we also – to understand any given biology – have to develop approaches that will isolate that biology so we can understand it. And one of our challenges is that we do not really have good models of those neurobiological aspects of MS to study. The EAE, for instance, which recapitulates some of the features of MS, has not really been shown to recapitulate those particular features that we're discussing.

 

MSDF

Finally, let me get back to one thing you mentioned that if you can identify the antigens of interest that are either spurring an attack or being targets of an attack the idea would be to find specific ways to approach those antigens. Now we have certain drugs that will deplete B cells, and they show benefit. We have certain drugs that will keep trafficking down cell adhesion molecules, and those seem to have benefit. Is there a focus on any particular antigens at this point and any particular approaches (clonal deletion, any sort of small molecules)? Where's that going?

 

Dr. Bar-Or

Well there are a number, and I probably won't be able to summarize all of them here. But there are generally several different strategies that try to target the immune system in a much more selective way than most of the approved therapies, including the not yet approved B-cell depleting approach which, of course, is more specific than targeting cells beyond B cells but is still depleting quite a few cells. Many of the B cells in the circulation, at least, are depleted. One extension to what you had raised is that it's fascinating to see how different approaches can achieve benefit of decreasing new disease activity, and we need to be able to sit back on a regular basis and integrate the insights from all of the successful, as well as unsuccessful, therapeutic interventions, including those that were not only unsuccessful in limiting new disease activity but the occasion where they increased new disease activity. What would appear initially paradoxical. Understanding all of that will give us very important insights into the disease itself. As far as antigen-specific approaches, one way is if you know what the antigen is – which, of course, we don't really know but we can hypothesize – you can try to develop induction of regulatory cells with that specificity or killing off or creating a state of unresponsiveness, also know as (18:40) of the effector specific cells or a combination of the two. There are different strategies that people have tried to use that are based, for instance, on the requirement of a T cell during activation to have an antigen-presenting cell present the antigen. And the profile of molecules both through contact and through secretion that the T cell can then receive in that environment of interaction with the antigen-presenting cell can often define the response profile, subsequently, of that cell. And if certain molecules such as costimulatory molecules are not present in that interaction or modulated, you might actually shut the cell down – you may not kill it, but it will be unresponsive or hyperresponsive – and that would be one strategy. Another, for instance, is to say well I don't know exactly which particular antigen, but I think it's myelin antigens. Let me get out of a patient's blood their immune cells and stimulate them to a variety of potential antigens, and whatever grows will reflect what grows in that person against the CNS antigens. And use that in a way to modify them so that they cannot cause problems and inject them back into a patient almost like a vaccine with a view that you are now giving that person whatever their T cells were that could respond to myelin, and their immune system now will respond to them and kill them and kill any other such cells that are present in the body leaving the rest of the immune system intact. And will that limit that person's ability to respond to their myelin? That again, is individualized medicine, which is one of the hot areas to pursue in the future, recognizing that if we hang our hat on a single target that may be true for one person but not for others or may be true for a person at some point in their illness but is not the predominant target later on. And so I think that using these kinds of approaches, which recognize the specificity or the selectivity, at least, as potential but also that there are very likely to be differences across individuals and maybe even with the same individual over time. And to try to individualize the therapy that is going to be most suitable for that person at that time. 

 

MSDF

Thank you, Dr. Bar-Or.

 

[transition music]

 

Thank you for listening to Episode Nine of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

[outro music]

[intro music]

 

Host – Dan Keller

Hello, and welcome to Episode Eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with researcher, Wendy Macklin, whose team studies myelination and demyelination in zebrafish and mouse animal models. But to begin, here is a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org.

 

As listeners may already be aware, a new study suggested that infection with HIV is associated with a lower risk of developing MS. Researchers looked at a large sample of hospital records and found that individuals infected with HIV had a 62% lower risk of MS than HIV-negative individuals who were matched for age, gender, region, and socioeconomic status. The researchers think that antiretroviral drugs might be causing the protective effect, though it’s possible the infection with HIV itself somehow protects against developing MS. Antiretroviral drugs may attack some ancient viral genes thought to trigger MS and other autoimmune diseases.

 

Science journalist, Ricki Lewis, covered a study of patients with a rare mitochondrial eye disease that may be entwined with MS. The disease called Leber hereditary optic neuropathy, LHON, is a degenerative eye disease that causes progressive loss of vision. But in some patients, the disease can also cause MS-like symptoms. Researchers performed MRIs on patients with LHON and found that their white matter lesions resembled MS, possibly providing an early snapshot of MS. The similarity of the diseases has also led some researchers to question whether they share a pathogenesis, but the rarity of LHON and MS developing in the same person is shifting the opinion towards calling any comorbidity of the diseases just a coincidence.

 

In a recent post in MS Patient, Ph.D., blogger Griselda Zuccarino-Catania followed up her feature on DMTs in pregnancy with her own personal debate on whether to continue her DMT while breastfeeding. In her post, she profiles researcher Thomas Hale, who studies drug concentrations in breast milk. He’s found that concentrations in a woman’s blood plasma are associated with the concentrations in her breast milk. These levels can be used to assess the risk any drug might have to infants.

 

[transition music]

 

Now for the interview. Science journalist, Carol Morton, met with Wendy Macklin at the Glia Meeting in Cold Spring Harbor, New York. She and Dr. Macklin discussed new research in myelination using the mTOR cell apoptosis pathway, the feasibility of a remyelinating drug, and her work with an unusual animal model for modeling MS – the zebrafish. [Note: the word "apoptosis" is incorrect and should not have appeared in the introduction to Dr. Macklin's interview. While it's impractical to remove it from the already-released audio podcast, we are correcting the error here, in this transcript.--Editor]

 

Interviewer – Carol Morton

There are not that many MS researchers who work with that.

 

Interviewee – Wendy Macklin

No, and there are times when you have to suggest that there is relevance to multiple sclerosis for looking at little two-inch fish. But they do. They provide really important information because you're not even looking at the two-inch fish; you're looking at the little, teeny tiny larva and embryos, but they are optically clear. So some of the new technologies use these green fluorescent proteins that originally were identified in jellyfish that make the jellyfish fluoresce at night. If you shine a certain wavelength of light, they turn green. And so, you can do that in a live animal, in a live fish; and in fact, some of the stuff that we were hearing today was even doing it in the mouse, but there you have to actually be able to get the microscope so you can actually see into the mouse brain. But in the fish, everything is transparent; so you can see it no matter what. So you just put the fish in a microscope environment, and you can watch cells, and you can take movies of cells moving, cells trying to make new processes, and cells wrapping around axons. And so you can watch this in realtime.

 

MSDF

You recently had a really interesting paper. Do you want to talk about...?

 

Dr. Macklin

So that paper came out of a project that we'd started a long time ago that was focused on understanding how one particular protein, Akt – which does many, many things in cells – regulates oligodendrocytes, which are the cells that make myelin. And it does many things; we thought it was involving in a survival element; and so we thought maybe we could find things that would help the oligodendrocytes survive immune attacks, survive things better and not die. And so we created a mouse where we overexpressed that protein in the oligodendrocyte. And instead, actually, what happened it did not change the survival of the cells at all; it changed how much myelin they made. And in fact, it drove the cells to make too much myelin. And in fact, if that becomes pathologic, the animals actually die when they're about a year old because they have too much myelin, and it's filling up their brain. So it's a dramatic change. And so, then we began to drill down to see well what is it about that molecule because it does many things? This particular hypermyelination syndrome was really feeding down through the mTOR pathway. And so, if you knockout parts of the mTOR pathway in the oligodendrocytes, the spinal cord is far worse and makes much less myelin and does not really generate the right kind of myelin. Whereas other parts of the brain are doing just fine or seem to be doing just fine. So one of the questions is why is this anymore damaged by this change in the cell? So the oligodendrocyte is identifying an axon and then wrapping around and making myelin, and that's what's the key question in MS is how to make sure that cell continues to make myelin. And we now have a system where we have changed the axons in some way – using again this mTOR pathway – and those axons don't encourage the oligodendrocyte to make myelin. So now we have a system where we can go in and try and figure out well what's fundamentally changed about those axons that they say don't myelinate me; whereas the oligodendrocytes in other parts of the nervous system are doing just fine making myelin.

 

MSDF

Now after the session this morning, I'm actually wondering if myelin making is now the goal, or has the goal…is the goal changing as people find out more for for therapeutic?

 

Dr. Macklin

I would say we don't know. So if you look in MS tissue, you see that where there's demyelination there still are oligodendrocyte progenitor cells, and there still are the cells that are trying to make myelin, the premyelinating cells. There's small numbers relative to the normal tissue, and they don't make myelin. So is that because we don't have enough cells? Is that because they have an inhibitor that's preventing them in that environment, or because they're not getting some positive signal? So I would still say the question of understanding how myelination is regulated has huge clinical relevance.

 

MSDF

Recently you went to another meeting that was really focused on myelination as a therapeutic problem, a therapeutic target.

 

Dr. Macklin

Right.

 

MSDF

In addition to knowing what's happening with the cells and the molecules in the environment in the brain, there's some other issues in getting myelin-making drugs through clinical testing.

 

Dr. Macklin

Yeah. In contrast to many of the other neurologic diseases, there are disease-modifying drugs out there for MS, but they almost all – at the current time – hit the immune component, which is absolutely essential and is definitely important. But even if you got rid of 100% of the immune component of MS, you still would have damage in the brain. And there is a good deal of evidence that the myelin not only does it allow better conduction of these axons, but it also provides all sorts of support. Metabolic it's providing energy to the axons; it provides a great many things to the axons that help the axons survive, which are part of the neurons. So if there is really still serious damage, you want to figure out some way to repair that. And so there are a couple of clinical trials actually going on right now that are looking at drugs that might enhance the remyelination in patients. And so, some of the things that we're doing – looking both in the fish as well as in the mouse – are pathways that could be targeted for therapeutics that might help you to enhance myelination. One of the big themes that came out of that meeting last month was that if you had the perfect therapy for remyelination – you know that it works well in the zebrafish; you know it works well in the mouse – you can get other models that allow you to look at remyelination in a number of different contexts. You have to get those to patients and see if they actually do create new myelin. In patients, the problem is that the current imaging modalities for patients, MRI, is measuring water. And where you have myelin there is less water because of the way myelin works. It's hard to know exactly why there's less water where you're looking in MRI. So there's a variety of different approaches. There's new techniques with MRI. There's even some new PET techniques – which are clearly experimental at this stage – to try to really be able to show new myelin. And part of that meeting was really if we had the perfect therapy how would we prove it in a clinical trial? You can show clinical improvement, which is great, but is that because of you've changed the immune system, because you've changed other aspects of the patient, or you really have new myelin? That's currently still a really hard problem in terms of the the clinical end of things to really be able to prove that. Nevertheless, people are developing these kinds of drugs, and as I said a couple of them are in clinical trial right now.

 

MSDF

Looking at your animal models, the ways that you have evaluating more or less myelin are ways are ways that can't be translated to people…

 

Dr. Macklin

Well some of them are. I mean that's really where some of this work is going is trying to figure out how to use either MRI or PET imaging of live animals, and then you can go and test. And you think you have a signal that tells you you have increased myelin then you can actually go in and check and see – at the tissue level – is there really new myelin? So you can validate some of these imaging modalities that way. But you you will always have to go eventually to the patients and be able to really demonstrate that that particular way of imaging the tissue proved in in an animal model really does mean something in the patient as well.

 

MSDF

I've seen those little mouse MRIs.

 

Dr. Macklin

They're so adorable.

 

MSDF

They are.

 

Dr. Macklin

And they definitely show you something. They definitely show you something. And some of the PET work…the PET work is more specifically directed to myelin so you can have a PET ligand, which shows up in PET imaging, that just literally binds only to myelin or binds predominantly to myelin, and it will go into the tissue, and it will bind there. And that actually gives you some fairly discrete imaging that because you know it's a molecule that only binds to myelin when you see that signal in a particular place you know that that is myelin. And if you see more of a signal, then you know that that's more myelin. So those are really interesting approaches, and they're very much more directed to being able to specifically say that's myelin that you're seeing. But in the clinical context, those kinds of approaches are being worked on, but they're still very early stages. In terms of trying to set up a clinical trial, those kinds of approaches may be the way you'll go eventually, but today you couldn't do it that way.

 

MSDF

Anything else that I should be asking, or that you wanted to add that would in in this context that would be interesting?

 

Dr. Macklin

Well I mean I think at this stage  there are other issues of the question of so much of the work is done on myelination, which is crucial during development, and it's absolutely essential. And problems with normal myelination during development result in really serious brain problems. There are ways to study developmental myelination: in the fish, in the mouse, in a variety of different ways. And then there's a series of adult ways of getting rid of myelin to look at remyelination. And so, the overwhelming perspective has always been well whatever you learn from the myelination during development would be exactly what you would need to know about for the remyelination in the adult. And much of that's true. I mean you have to get the cells, you have to get the cells to proliferate, you have to get them to the right place. But there are now data that suggest that there are definite differences in the way the adult cells are responding to their overall environment, which is totally different than from the developmental environment. The cells may be very similar, but in the developing environment the many things are changing all of the time – the nerve cells, all of the different cells are changing, the brain is getting bigger – there's all sorts of changes. And in a damaged adult brain, you see certain differences that do seem to be real in terms of the way the signaling pathways are that would regulate how the myelin is generated in the remyelinating context versus in the developmental context. So we do need to go back and forth even the ones of us who work on the fish. We need to be able to look and see some adult context that's a demyelination/remyelination context that those same things that you're seeing developmentally are important in the adult.

 

MSDF

That is interesting because I have heard people say well you recapitulate, you want to recapitulate the…

 

Dr. Macklin

Yes, and it does. It…

 

MSDF

…the developmental pattern.

 

Dr. Macklin

Right.

 

MSDF

So that's interesting in that. Okay, well that's fabulous. Well, thank you for taking the time to do this.

 

Dr. Macklin

Okay. Certainly.

 

MSDF

It was wonderful.

 

Dr. Macklin

I hope it's useful for you.

 

MSDF

Okay, great.

 

[transition music]

 

Thank you for listening to Episode Eight of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

[outro music]

[intro music]

 

Host – Dan Keller 

Hello, and welcome to Episode Seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s podcast features an interview with neurologist, Dr. Daniel Kantor. But to begin, here's a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org.

 

At MSDF, we publish short, medium, and long articles. The longest News Synthesis articles cover an entire area of MS research. In one recent News Synthesis, science journalist Cynthia McKelvey, provided a primer on epigenetics. Epigenetic modifications are defined as any change to gene expression that happens without altering the 

DNA sequence, and they could be the key to understanding heterogeneity in MS. Though the literature on the role of epigenetics in MS is growing, the field remains in its infancy and is not very well understood by many MS researchers and clinicians.

 

The medium-length articles we call New Findings, and they focus on either a single study or a small group of closely related studies along with comments from experts not directly involved in the studies. An excellent example by Science journalist, Mitch Leslie, explores an iPad app that may become a more convenient alternative to the much maligned Expanded Disability Status Scale, the EDSS. The app mimics four tests in the Multiple Sclerosis Functional Composite test. In an initial study, the app was sensitive enough to discern people with MS from healthy controls. If future trials are successful, it could allow patients to test themselves at home. It could also streamline data collection making the app useful to researchers as well. Our article includes a video demonstrating the app in action.

 

Then there are the News Briefs—short, meaty, and easy to digest summaries of noteworthy studies. For example, we reported on a large international survey that recorded a high statistical correlation between physical activity and health-related quality of life in MS patients. Another news brief looked at a study showing that evaluating a patient’s treatment preferences may play a key role in how long he or she will stick with a disease modifying treatment. We also reported on a study that described differences in overall brain atrophy between MS patients with oligoclonal bands and those lacking them.

 

Now for the interview. Dr. Daniel Kantor is a neurologist based at the Neurologique Foundation in Florida who is concerned with MS patients’ access to care. Dr. Kantor met with MSDF editor, Bob Finn, to discuss this issue.

 

Interviewer – Bob Finn

Dr. Kantor, welcome

 

Interviewee – Daniel Kantor

Thank you.

 

MSDF 

In a recent article in MS Focus, you wrote that there are three types of access to care. What are they?

 

Dr. Kantor 

Access to care means many things. Sometimes people think access to care just means access to medications. But access to care actually means access to physicians, access to medications, and then access to all the other diagnostics and other types of testing.

 

MSDF

And how would you grade the US healthcare system on each of those as it relates to MS patients on each of those factors?

 

Dr. Kantor

2014 has been an important year with the Affordable Care Act as well as with other federal legislation as well as state legislation that's happened. Access to care for some patients has gotten better. People who maybe couldn't get insurance have been able to get it. For a lot of people, though, their access to care has either remained the same or actually their access has come down. What I mean by that is somebody who could see the physician of their choice in the past now, in 2014, has found it increasingly difficult to have access to physicians who are familiar with their care, familiar with their disease state, and familiar with the treatments that are out there. 

 

MSDF

You mentioned the Affordable Care Act. How is that specifically affecting access to treatments, access to physicians, access to diagnostics?

 

Dr. Kantor

The Affordable Care Act did several things. One of the things that happened in the Affordable Care Act was the creation of these exchanges or the marketplace. So in states that either ran their own marketplace or that go with the federal marketplace, there are plans that are really "stripped down" insurance plans. And that means that there's more restricted networks – meaning the patient has less choice when it comes to who to see about their disease state – and there's also sometimes more restrictive choices in terms of the medications. So you have less physicians to offer them care, maybe not physicians who specialize in multiple sclerosis, and then that physician also has less choices of what to use. So as you can imagine, those things get compounded, and a patient may have a lot less access to care than they would have had otherwise. A simple example is a patient who did not have insurance and now has insurance. So a patient who didn't have insurance before they've gained access because now they carry a plastic insurance card. But while they may have been paying a reasonable sum to a physician to see them with a cash pay, now that physician is not offered on their health insurance plan. While they may have been part of a patient assistance program with many of the pharmaceutical manufacturers, they may or may not still be eligible for those same patient assistance programs. Meaning that a drug that may have been free to them – or very low priced – may be even more expensive to them now. 

 

MSDF

At MSDF, we recently ran an article about a study; it was a survey of neurologists. And the survey was looking at a number of different things. But the neurologists were saying that their patients were happy with fingolimod but not happy with their insurance companies giving them access to fingolimod. What other sorts of issues like that are arising in MS?

 

Dr. Kantor

I think it's a perfect example. Prior to 1993, we had no disease-modifying therapies that were FDA approved. Since 1993, we now have 10 separate branded products. That's an amazing leap forward. Not many fields in medicine have seen that kind of increase and certainly not in the world of neurology. For many patients with other neurological conditions – like Huntington’s disease, amyotrophic lateral sclerosis or Lou Gehrig’s disease, even stroke – they look at MS, and they're jealous. They have seen such an increase in the amount of research. At the same time, however, we see a decrease in the practice. We see it being harder and harder to actually practice good MS clinical care. And so, while patients may have access in some ways to medications that have even more efficacy than our traditional medications, if a patient can't get their medication or has to go through many, many insurance hoops to get there, then that's not good for them.

 

MSDF

What's the solution?

 

Dr. Kantor

The solution really is the neurology, physician, nurse practitioner, and physician assistant and community working alongside the patient community together and engaging our colleagues in the managed care world. Like it or not, in America, healthcare is usually paid by somebody else. Most people do not walk into a hospital or walk into a doctor's office and write the payment themselves. They are either part of an employer group – where the employer is frankly handling much of the payment – or now they're part of exchanges, or they may even be part of a federal program like Medicare or a state program like Medicaid. So the client for the doctor is not really the patient. Our patients are our patient; and we have a Hippocratic Oath; and we have a long, long time of tradition of what we do for that physician/patient relationship. But it's not really a client relationship. That might be good/that might be bad, but it's the fact. In fact, for most practicing physicians, most practicing clinicians, our client is actually the insurance company. And so that means that there's some disconnect between what a patient might think they want and even what the physician might think they want for the patient and what the patient actually gets. So what we need to do, though, is engage these managed care organizations better in terms of recognizing that things like step edits, like prior authorizations those are here to stay. Sometimes some neurologists see them as so unethical that the real prior authorization should be the doctor's prescription. The fact is that that's not the case. And it's going to be very hard to change that system (9:26) unless the person who's actually paying is the actual patient. And so recognizing that managed care organizations are there to manage their medical costs we need to work better at giving them the tools they need. We think that there's no guidelines for treatment of MS; there actually are; there are many guidelines. Each state – if you look at the major insurance company in that state – their prior authorization and utilization management criteria that is the most commonly used guideline for multiple sclerosis in that state. So while we may think, as physicians, it doesn't exist, it does exist; it's just not being written by us. These are being written by pharmacists at either pharmacy benefit management companies or pharmacists at insurance companies, and they're deciding the fate of our patients. We need to take a more proactive stance and work together at developing guidelines that can make sense and that have also "outs". What I mean by that is even if you say that we have a treatment algorithm that works for most patients there's always going to be patients who for some reason or other you don't want to put them through that algorithm. An example may be if you're going to start a medicine that has a potentially high chance for a certain side effect – and you think from past experience that that patient may have that side effect because they've been on similar medications with a similar side effect – then you may not want to put them through that algorithm. You may want to say well they haven't failed the medicine yet, they haven't had an intolerable side effect from this medicine, but they've had from a similar medication. And that becomes a big issue, for example, in the use of one of the oral medication, dimethyl fumarate – also called BG-12 or by the brand name of Tecfidera – where we do see significant GI side effects. For a lot of people, we don't; for most people they tolerate it well. But if you have a patient who has already shown you on multiple other medications for different symptoms that they have sensitive stomach, then even without a diagnosis of Crohn’s disease or celiac, you still would probably want to avoid using that medication. So that's an example where it's not a contraindication listed on the label, it's not an absolute contraindication – and it may not even be considered a relative contraindication – but in the physicians' opinion that patient would have a negative outcome because of that medication that's where they shouldn't go through that algorithm in the same way.

 

MSDF

How successful are you at convincing insurance companies of that?

 

Dr. Kantor

I think we're getting increasingly successful. In 2009, we started a group which was at first called the SouthEastern MS Consortium, or seMSc, sort of like the SEC in football. And then Texas A&M entered the SEC in football so we expanded to the Southern MS Consortium. And we go from Texas east and Delaware south; we take the most liberal definition of the South. Now there are members from California, Minnesota, Pennsylvania, and we're actually about to relaunch and rebrand as the Medical Partnership for MS. And the idea was that prior to this MS neurologists, as well as nurse practitioners, physician assistants, speech therapists, physical and occupational therapists, case managers, social works didn't feel like they had a voice when it came to advocacy for their patients. They felt like the existing organizations didn't always reflect what they're going through and what their patients are going through with taking a proactive stance on some difficult issues but by engaging in a collegial way with the insurance companies. Instead of taking in a stance that every medication should be available for every single patient, we've taken a more reasoned approach of while that may be in an ideal world that's not the world we live in. And so, let's look at the different utilization criteria, utilization management criteria, of the different insurance companies and work with them on a one-by-one basis. So we have constant conversations with insurers throughout this country.

 

MSDF 

Dr. Kantor, I thank you very much.

 

Dr. Kantor

Thank you for having me.

 

[transition music]

 

Thank you for listening to Episode Seven of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations. 

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

[outro music] 

 

[intro music]

 

Host – Dan Keller

Hello, and welcome to Episode Six of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s Podcast features an interview with Dr. Jeffrey Dunn, who explores the prospect of personalized medicine in MS. But to begin, here’s a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org.

 

Recently, blogger Emily Willingham shared a person experience with MRI interpretation in our blog, MS Patient, Ph.D. She wrote, “I’ve come to realize in my various dealings with MRI reports that neuroradiologists are like economists; everyone has an opinion and no two readers will agree on what they see in exactly the same data.” Willingham, a developmental biologist, provides a unique view into the life of an MS patient. Her experiences bring a first-person perspective of MS, while her scientific background informs her insights in a way that many researchers and clinicians may find valuable.

 

We’d also like to bring your attention to the data visualization section of the MSDF website. Under the research resources tab, you can find a series of interactive data visualizations useful for MS researchers. One visualization aggregates 106 clinical trials. You can organize the data by the compound, phase, population, or even the funding. Our latest visualization is of the natural history of MS symptoms. The interactive bar chart allows you to see the change of various symptom severity in MS over a 30-year period.

 

Also in research resources, check out the drug development pipeline. This is where we keep detailed information on, at last count, 40 drugs currently in development or on the market for MS. This database, which is updated daily as new information becomes available, contains a wealth of data on each agent. This includes the agent’s class, its intended target and routes of administration, its regulatory status and commercial history, its chemical properties, mechanism of action and adverse effects, and all its clinical trials.

 

Now for the interview. Dr. Jeffrey Dunn is a Professor of Neurology and Neurological Sciences at Stanford University. He met with MSDF editor Bob Finn to discuss the use of biomarkers and personalized medicine. But first he shared a little history.

 

Interviewee – Jeffrey Dunn

So, in the history of multiple sclerosis, when cases of CNS demyelinating disease were first discovered, they were discovered as isolated case instances at a number of different and variable institutions throughout Europe and in the United States. The doctors knew of the patients’ symptoms, of course, because they had cared for them. Many of these patients went on to pathology examination, and multiple cases of areas of inflammation or even scar formation were seen within the central nervous system. These cases from the mid-1800s and into the late-1800s were described as isolated instances. And the physician who is given credit for the discovery of what we now know to be multiple sclerosis was Dr. John-Martin Charcot in Paris, because he had had the experience of a very close relationship with a patient he named Mademoiselle V. He had known that she had had a tremor and ataxia and eye movement abnormalities, so Charcot knew his patient’s phenotype, her clinical manifestations, very well, and specifically had seen evidence of eye movement abnormalities, tremor, and ataxia. She had consented to have her nervous system evaluated pathologically, and so Charcot was able to make a connection between what she had looked like in life, and then what her brain and spinal cord had looked like after she had passed away.

 

It’s that clinicopathologic correlation that really was a paradigm-buster at the time. And Charcot found palpably hard spots – areas of gliosis or scar formation – that occurred in plaques and patches throughout the spinal cord and brain (and cerebellum in this case). He called the disease almost an adjective really; he called it “la sclérose en plaques”, which is French for sclerosis – meaning hard spots essentially – in plaques. So hard spots was the disease. Multiple sclerosis is really an adjective more than a diagnosis. But in the early 20th Century leading up to the mid-20th century, there was increasing recognition on the basis of these isolated case reports that this disease that was now increasingly being called multiple sclerosis might be far more common than people had realized, and great credit needs to be given to Sylvia Lawry, who as you know was the founder of the National Multiple Sclerosis Society. The National MS Society was put together to try to bring physicians together to create a forum by which they could crosstalk, share the anecdotal information each of them had compiled, and come up with a more systematic review so that the disease could be better described and so that treatments could be more likely discovered. This was a huge step forward in terms of our discovery and ability to diagnosis and ultimately later to treat MS, but it created a framework that said that MS was, in some respects, one disease.

 

Now all of us even today, I would say, as physicians are trained that MS is a distinct disease; that it’s one type of disease with many variations according to individuals, but I think we’re actually at the very beginning of a very important paradigm shift in this consideration. There’s a difference, of course, between a disease and a syndrome. A disease is a quantifiable isolated entity – a classic example might be a genetic disorder caused by a single mutation in a coding sequence of DNA – whereas a syndrome is probably a collection of different but closely related diseases. I think there’s increasing evidence now, an increasing recognition that MS may be very heterogeneous and variable across individuals; I don’t think there would be any argument among my colleagues that MS is a heterogeneous process. My suggestion to you is that now, I think, we’re at the threshold of a paradigm that says that MS should not be regarded as a monolith or a single pathologic entity, but maybe more as a Stonehenge; a collection of closely related conditions that share some common pathology, but that need to be considered on an individual basis.

 

At the clinical, radiologic, immunologic, and pathologic levels we have evidence that MS is very heterogeneous among individuals. I think the theory that we now need to proceed according to is that multiple sclerosis is not one disease entity, but a number of different conditions. This idea and paradigm of personalized medicine is gaining traction. Our oncology colleagues who treat cancer have used this with some great and promising success in terms of applying optimum regimens and chemotherapeutic protocols to their patients, but I think there’s tremendous opportunity in multiple sclerosis to practice personalized medicine, because I think that the process of MS is a personalized one in which there are unique and eminently measurable proteins or protein profiles one day we’ll be able to identify, and hopefully that day is soon, and we can use that as the rationale for our prescription for the patients.

 

Interviewer – Bob Finn

So when some people think about biomarkers, they think about an individual protein or some other biological signal that will be prognostic or in some other way tell you about what the patient is experiencing or might experience. It sounds to me like you’re talking about not an individual biomarker, but a constellation of biomarkers that would provide a fingerprint. Am I right about that?

 

Dr. Dunn

I think so. Just as the disease pathogenesis itself is heterogeneous, I don’t think that one single protein would be able to help us. What I would foresee as an individual approaches us, that we might do a panel. There’s a series of questions that has to be asked. The immune process itself is sequential and acts, I think, as a cascade, and we have some biomarkers today that are available. I think you could argue them as biomarkers that help us in decision-making, that help the clinician decide what might be the best therapy, at least in terms of risk-benefit balance, but we just don’t have enough of them to be able to make the kinds of personalized decisions that I think we all hope we’ll be able to make one day.

 

MSDF

Would you mention a couple of the ones that are – or some of the ones – that are available now?

 

Dr. Dunn

So one example that I think would be well agreed on is the presence or absence of JC virus infection that can now be measured by a two-step ELISA assay, with a false-positive rate of an estimated 2.5%. One of the great challenges we face in treating MS is that we have to, in some respects, down-regulate the immune system to protect the brain and central nervous system, but we can’t overshoot the mark to cause a systemic immunosuppression. Immunosuppression can manifest in a number of different ways, including opportunistic infections and even malignancy. One of the most lethal and daunting of the opportunistic infections is a condition called progressive multifocal leukoencephalopathy – that’s precisely why we tend to call that PML instead, three syllables is far preferable – and that condition is caused by an infection of an otherwise relatively benign virus called JC virus, that if it gets into the central nervous system and begins to affect oligodendrocytes and cells of the central nervous system, can cause rapid intracellular proliferation and damage to the brain; that can spread geometrically throughout the brain and can cause very profound brain damage, and sometimes cases of death as well.

 

We’ve known of PML previously in patients with lymphoma and also in patients with untreated HIV infection who had severe and advancing immunosuppression. But we’ve seen this same PML condition in immunocompetent patients who have been treated with some of the agents that we might use for multiple sclerosis. This concern is not unique to MS, but it’s a concern with any immunotherapy that you use. The ability to measure whether a patient has previously been infected with a JC virus or not helps us in the risk-benefit balance considerations we have to make on behalf of our patients. It’s known that the absence of evidence of a JC virus infection is associated with a markedly decreased risk of PML, whereas its presence means that’s an active consideration in our prescribing.

 

 Now that, I think, functions as a biomarker. Any time you might see an elevation of a measurable protein or another biomarker in general that normalizes with remission that gives you the opportunity to suggest that that either might be a therapeutic target – so let’s just call it protein X, for example, just for simplification and clarification. If a patient having an MS attack has a measurable increase in protein X in their blood which then now returns to normal or what had been their previous baseline in remission, that tells the clinician investigator that protein X might either be part of the immunologic cascade that causes the MS attack, and therefore suggests that the ability to intervene, down-regulate, or modify the expression of protein X may help with disease pathogenesis, OR it could also mean, or it could emerge as a candidate as a tool of assessment for disease status, so that one question we always have to ask as clinicians when we start patient on any given therapy or just in following them is how are they doing. Of course, that’s a primary mandate for the clinician taking care of patients.

 

Today, we do that by asking how they’re feeling, we strive to get into quality of life metrics with them, we also turn to their examination findings to look for interval change, and we look at MRI to see if there’s been a change there, with the hope that we’re seeing no evidence of disease activity. But the field of multiple sclerosis does not have its own version of a hemoglobin A1c, such as our endocrinologists have. In that scenario for those that aren’t familiar with it, A1c can be a value obtained literally with a single drop of blood that tells the practicing clinician caring for the patient what the average blood sugar of that patient has been over a substantial period of time prior to the time of their clinical encounter. So it helps the clinician make wise judgments and counsel to the patient regarding the optimum way to treat their diabetes, whether adjustments have to be made in their diet or in their prescription medications.

 

We don’t have such a thing in multiple sclerosis today. If we could find such a thing, it would make our care, I think, far superior in its quality. I think it would make physicians’ advice to our patients far more wise, and it would make the entire medical enterprise of caring for the MS patient less expensive, because we wouldn’t have to resort to important but still somewhat stodgy and expensive technologies like serial MRIs done with what could be high-frequency for the patient. Serial MRIs are safe for the patient, but you can see that if we could identify such a biomarker as that, if that were possible, I think that would have revolutionary implications for our care of the MS patient, not just in reducing medical costs – that’s an important goal – but the more important goal and what physicians need to focus on is superior advice, improved advice and counsel to the patients that are in our care.

 

 

MSDF

So you and I are both old enough to remember when the Human Genome Project was proposed, and one of the values of the Human Genome Project that was articulated was that it would usher in an era of personalized medicine. Now it’s 13 years or so after the Human Genome Project has been completed, and, arguably, that promise has never been realized. How much longer will it take in multiple sclerosis to realize an era of personalized medicine?

 

Dr. Dunn

The short answer is I don’t know, but there’s some important considerations to be made along the way. One fact is there are approximately 25,000 genes in the human body, but there are an estimated 500,000 proteins. The reason for the difference is that after an original protein is manufactured on the basis of the blueprint of DNA, it can be modified in transcription and translation. For those of you in your field, this would be post-production modifications. The same thing happens with proteins, and what that means is that the field of proteomics, you could argue, is 20 times more sensitive than the field of genomics if the ratio is 25,000 to 500,000 genes to proteins in the human body, respectively.

 

MS does have a genetic component, and that’s been proven by research in this past two decades by our country’s leading researchers, but the genetic input of MS is not the only answer; MS is only partially a genetic disease. It seems to be, in my own opinion and I think it’s shared by my colleagues – many of them, most of them perhaps – is that MS is primarily an environmental condition. The greatest risk of obtaining MS is not so much that family members are affected, though cases of that have happened and happen regularly, it seems to be more related to environment, where one lives. Now you may know that epidemiologically, MS is almost absent, or very sparse, at the equator, but in moving north and south on Earth, the greater that one moves away from the equator, the greater the prevalence of MS. And right about the 35th parallel or so both north and south of the equator, there appears to be a relatively large increase in how much MS there is. And that’s true, to the best of our knowledge, all the way around the world.

 

And so if MS is more of an environmental condition than a genetic one – although it’s both – then I think a genetic assay may be part, but not likely to be all of the answer, and the promise of going to a more sensitive assay to get into the post-transcription and post-translational modification that takes place in human molecules, which ultimately are the language of how the immune system affects our nervous system, is going to be and prove to be a more enriched and more promising field of inquiry.

 

MSDF

I wonder if you can mention some of the labs that are doing the most promising work in this area.

 

Dr. Dunn

I’m pleased to say that there are labs throughout the world that I think are doing research in this. Within the United States – I don’t want to leave anybody out – but I think that special kudos need to be given to the Mayo Clinic. I think on the east coast the Partners Program of the Harvard Medical Schools are very interested in this field; Johns Hopkins is doing work that I think is exemplary. Out west, our colleagues at UCSF. And, of course, I have to give special kudos to my colleagues at Stanford University. These are places that are publishing in translational medicine the bench-to-bedside framework in which discoveries that are being made at the level of the bench, there’s an active effort being made to try to translate that to human care. I’m very sensitive to the idea of excluding anybody, because I think that this is really an international search, and it’s going to require multilevel of collaboration. So I hope that as we go forward, we’ll be able to really work together.

 

I mentioned just a moment ago, I think practice of personalized medicine in this field is going to require not one discovery, it’s going to require a panel, perhaps, of different measurable biomarkers. I don’t anticipate one single lab is going to be able to discover all of those biomarkers, I think we’ll get one discovery from one place, one from another, one from another. And it’s going to require a transcendent collaboration between institutions and individuals and researchers and investigators to bring it all together for the collective good.

 

MSDF

Dr. Dunn, thank you very much.

 

Dr. Dunn

Okay, alright, thank you very much, Bob.

 

[transition music]

 

Thank you for listening to Episode Six of Multiple Sclerosis Discovery. This Podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

[outro music]

[intro music]

 

Host – Dan Keller 

Hello, and welcome to Episode Five of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m your host, Dan Keller. 

 

This week’s Podcast features an interview with Dr. Anne Cross, who reflects on the past year in MS research. But to begin, here’s a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org. 

 

Researchers have discovered that multiple sclerosis may have something in common with colon cancer; the Wnt pathway. It’s a genetic pathway important in development, stem cell maintenance, and cell differentiation. In colon cancer, the mutation of a mediator gene called APC causes the Wnt pathway to become overactive, leading to tumor formation. Now, researchers have discovered that a loss of function mutation of APC in the brain also leads to an overactive Wnt pathway, ultimately freezing oligodendrocyte progenitor cells in their undifferentiated state. 

 

Next, what disease-modifying therapies should women start or stop before pregnancy? In our latest news synthesis, we discuss the difficulties many women with MS have in deciding when to stop DMT before trying to conceive. Since it can take months, and even years, for a woman to conceive, it’s important that she spend the least amount of time off medication as possible to reduce the chance of relapse. Some drugs may be worth taking during pregnancy anyway, but it’s up to the neurologist to do a risk-benefit analysis for each patient. Nevertheless, many women opt to go off of DMT altogether to reduce the risk of adverse effects on the fetus.

 

Finally, we would like to direct your attention to funding opportunities on the MSDF webpage. Under the Professional Resources tab at msdiscovery.org, you can find a listing of various organizations offering funding for research grants, fellowship grants, and more. Currently, there are several opportunities offered from ECTRIMS with deadlines this winter. There are also several deadlines for funding from the National MS Society coming up in August. 

 

Now for the interview.

 

Interviewer – Bob Finn

This is Bob Finn. I’m here with Dr. Anne Cross of the Washington University in St. Louis. Dr. Cross will later today be giving a talk at the American Academy of Neurology meeting on what the year has been like in MS research. And, so, let me ask you briefly, what has the year been like? Has it been a good year, a bad year, an exciting year, a boring year?

 

Interviewee – Anne Cross 

I think it’s been a pretty good year. There have been some mainly good things, a couple of bad things, some rather interesting and unexpected things, too. I guess some of the good things involve genetics research papers that have come out identifying genes that are associated with risk of developing MS. That’s been kind of exciting. Actually, there were 48 new genes that were identified and published this year by the International MS Genetics Consortium, which is a very large group of international researchers that have amassed probably close to 30,000 genetic samples from MS patients over the years that they’ve been in existence, which is about 10 years, plus close to double that of controls. And all these MS patient samples are from patients who were well characterized and submitted by, generally, MS specialists. 

 

And that group did a study using something called the Immunochip, which is a genotyping array that was actually developed by a group of investigators who work on autoimmune disorders, so that array is very much weighted towards beings with immunologic function. So not too unexpectedly, all 48 of the newest identified genes all relate in some way to the immune system or are very closely linked to genes of immune function. But prior to that, the same group – the International MS Genetics Consortium – had identified about 50, a little over 50 genes that are associated with MS risk, and most of them were also related to genes of immune function. So I think together, all of this data certainly implicates the immune system, which we already knew, but I think things are certainly solidifying around that with the newest data.

 

MSDF 

Let me ask you, if they’re using techniques that are specific for immunological genes, are they missing other genes?

 

Dr. Cross 

They very well could be. The original studies that this group did which were published, the biggest study was published in the summer of 2011, did not do it in that fashion, though, they just did a genome-wide association study, and most of the genes that they identified were related to the immune system directly or indirectly. So, yes, I’m sure that some are being missed that aren’t related to the genes that are on this Immunochip microarray, but they’re trying to hone down a bit. 

 

And some of the other things that were discovered were that, well, they identified 5 allelic variants; the particular allelic variant was over 50% of the time associated with risk of MS. And they also identified in this latest search – well, the strongest association was with a gene that has immune function called Vcl-10 – they actually in this latest search rediscovered the same 50 or so that they had discovered before, so they were actually mostly in this Immunochip microarray.

 

MSDF 

So, aside from the genome-wide association studies, what else has been interesting in MS research this year?

 

Dr. Cross 

Well, I think some of the clinical trials that have been published in the past year, and also that are just ongoing and aren’t published yet, have been interesting. This past week, Dr. Rhonda Voskuhl, who’s from UCLA, spoke and presented for the first time ever recent data from a study of estriol, which is a pregnancy hormone that was added to glatiramer acetate in women with relapsing-remitting MS, and that was compared to placebo pills added to glatiramer acetate. And the results were pretty positive, especially in the first year when there was an almost 50% reduction in relapse rate in the group that received estriol plus glatiramer. And, you know, that’s, of course, based upon longstanding data that we’ve known, that women with MS who have relapsing disease have a much decreased relapse rate during pregnancy. And then Dr. Voskuhl had done a good bit of work with estriol, in particular, which is a fairly safe pregnancy estrogen hormone compared to some of the others, but it’s not available in the United States right now. 

 

MSDF 

You mentioned that there were some disappoints.

 

Dr. Cross 

At least for me, and probably for a lot of MS patients, the biggest disappointment was the failure of the FDA to approve a drug called alemtuzumab, which is a humanized monoclonal antibody against an antigen that’s on pretty much all the mononuclear cells of the immune system. And the US FDA failed to approve it, although, I believe, 32 countries and counting have approved it at this point, including Canada and Mexico and all of the countries of Western Europe, Australia, Brazil.

 

MSDF 

Have there been any interesting developments on the remyelination front?

 

Dr. Cross 

Yes, yes, yes. In fact, I hope to speak about that today. There are studies in early-phase trials right now of anti-LINGO-1, which is a humanized monoclonal antibody against a molecule called LINGO-1, which is found only in the central nervous system – at least that’s what the data says so far – and it’s expressed by oligodendroglial cells, or the cells that make central nervous system myelin. And, for whatever reason, it’s involved in inhibiting remyelination in the central nervous system. So the monoclonal antibody that inhibits it then enhances remyelination. And in mouse models it looked very good, and it also led to less injury to axons, or nerve fibers, so it had more than just a remyelinating effect. And it’s now in phase II studies in relapsing-remitting MS and optic neuritis patients. At least the relapsing-remitting MS study is fully enrolled, and so we’ll be looking forward to those results.

 

So another potential remyelinating agent is a little bit behind anti-LINGO-1. It’s called recombinant human IgM22, and it was developed from a natural IgM antibody that was discovered at Mayo Clinic that binds to a surface antigen on oligodendrocytes – the cells that make central nervous system myelin – and it enhances myelination in mouse models of demyelination, and, in fact, in some studies, just a single dose of that led to longstanding remyelination in the mouse model. So that’s in dose-finding studies in human beings at the present time, and hopefully will move forward from there.

 

Other exciting things, at least to me, are studies of stem cells that can be differentiated into different types of cells. And, at this point, you can actually take human skin cells or human fibroblasts and revert them back to stem cells; they’re called induced pluripotent stem cells. So you can actually take a person’s skin and do that, and then you can differentiate it forward into whatever cell type you want, really, these days; I mean, you can differentiate them into neurons. And in MS, we’re very interested in differentiating them into oligodendrocyte precursor cells – cells that form the cells that make central nervous system myelin. 

 

And a study that I plan to talk about this afternoon took such cells and made them into human oligodendrocyte precursor cells and put them into the central nervous systems of mice who had a genetic mutation in myelin basic proteins, so they are essentially unmyelinated. And these mice die very soon after being born, much earlier than normal, and they put these human cells in. They had to immunosuppress the mice so that they’d accept the human cells. But these cells actually made myelin, and it was functional myelin at least from the standpoint of wrapping around fairly normal-looking nerve fibers, axons, from the mice, and forming compact, normal-appearing myelin. So that particular group, they’re from New York State and they’re affiliated with several other medical centers, and they plan to get this into humans pretty soon. Their first project, however, is going to involve fetal stem cells first, because that was easier to get approved and moved forward on, and so I believe they’re already funded to do a three-center – all in New York State – stem cell study injecting such cells into the central nervous system of people with secondary progressive MS. 

 

MSDF 

Now some patients aren’t waiting for the studies, I understand, but what is your point-of-view about that?

 

Dr. Cross 

It depends on where they’re going and what they’re doing. I personally think there’s some shoddy research, some charlatans you might call them, out there who are taking the money and presenting false hopes to patients that I certainly disagree with. And I have one particular patient I know who went to another country and had stem cell therapy done in what she described as a very dirty environment. And luckily nothing bad happened to her from this experience, but nothing good happened either. I’m hoping that she’ll be able to get into some of these well-done, scientifically valid, protocol-driven studies that seem to have some promise. 

 

MSDF 

Any other interesting areas of MS research in the past year?

 

Dr. Cross 

I think the unexpected finding that I plan to talk about is an association of salt – sodium in particular, the sodium component of sodium chloride – in the development of a particular type of pathogenic T-cell that at least is related to the mouse model of MS called experimental autoimmune encephalomyelitis. These are Th17 cells and they’ve been shown to, at least in some models, cause the EAE model for MS. And it was found that if you increase the salt intake of mice that had been induced to develop this model and compared them to mice who weren’t getting extra salt in their diet, that the mice who got extra salt got disease earlier; they had a more severe course, they didn’t recover as well, and they had histologically when you looked at their central nervous systems, more cells infiltrating and just more damaging. So that was kind of interesting and quite unexpected, I would say. 

 

Two different groups of investigators sort of came up with that at the same time; I’m sure they were speaking to each other about it, that the studies came out right together. It certainly would be a modifiable environmental thing if it proves to be true, and perhaps even a little bit simple. And there is actually a scientific reason behind why this might occur. Well, there’s a response in the body by something called p38 MAP kinase in response to, like, many different stresses, but including among them osmotic stress which increased salt could cause. And that pathway that p38 MAP kinase is involved in eventually can lead to the induction of a particular kinase that is key to the development of Th17 cells. So it sort of all, you know, fits together. 

 

There are certainly some things that don’t fit with that. I think that certain areas of the world, for example, have very high salt intake and yet have low MS rates, but it may be that there’s this environmental factor. There probably are many different environmental factors that’s going together with a genetic predisposition, and those together are probably leading, perhaps, to MS. In any event, this will have to be proven by other groups, but if the association is true, it would certainly be modifiable.  

 

MSDF 

So looking ahead into the next year of MS research, what are you particularly looking forward to seeing?

 

Dr. Cross 

I’d like to see more data come out on some of the other oral agents; there are a couple that are in the pipeline that are being looked at that perhaps have other mechanisms of actions from what we have now. I’d like to see other studies funded for estriol so that perhaps it could come to the United States and be an adjunctive therapy probably for women with MS and probably pretty safe. I’m really hopeful – I’m not sure if it’ll be in the next year – that we’ll see some good data coming out from these scientifically valid stem cells projects to help people with progressive MS, and help people who have longstanding disability to recover some function; those are the people that really, really need help in the MS world right now.

 

MSDF 

Well, Dr. Cross, thank you very much.

 

Dr. Cross 

Thank you.

 

[transition music]

 

Thank you for listening to Episode Five of Multiple Sclerosis Discovery. This Podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. 

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

[outro music] 

 

[intro music]

 Host – Dan Keller

 

Hello, and welcome to Episode Four of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 This week’s Podcast features an interview with Dr. Michael Racke about the potassium channel Kir4.1 and its potential role in MS. But to begin, here’s a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org.

 

 Researchers at the University of California San Francisco have developed a new remyelination assay that allows high through-put drug screening. The assay takes advantage of oligodendrocyte’s tendency to wrap myelin around anything axon-shaped, such as plastic fibers and microscopic glass pillars. The assay has already identified several FDA-approved drugs as candidates for remyelination therapies, including an over-the-counter antihistamine now in phase II clinical trials.

 

In another article, we report on a new study that sheds light on the ameliorating effect of ultraviolet rays on inflammation and disease progression in mouse models of MS. In the study, MS patients sat in a therapeutic UV chamber for five sessions a week for six weeks. Even after one session, the patients had an increase in dendritic cells and regulatory T-cells. In follow-up studies with EAE mice, the researchers uncovered a possible mechanism by which these regulatory T-cells migrate to the central nervous system.

 

In addition to covering the latest in MS research, the MS Discovery Forum also curates news stories from around the web in our twice-weekly Research Roundup. Last week we wrote about the findings in phase III trials of daclizumab, a legal dispute between drug companies Acorda and Actavis, and a new collection of immunology papers from the journal PLOS. We also posted some social media advice as well as the amusing hashtag #yomanuscipt. Our favorite tweet: Yomanuscript is so bad the null hypothesis rejected it. Check out Research Roundup under the news brief section in the News and Future Directions tab on our website.

 

[transition music]

 

Now to the interview. Dr. Michael Racke is the Chair of the Department of Neurology at the medical school at Ohio State University. He’s here to discuss the latest findings of the potassium channel known as Kir4.1 and its implications for MS. MS Discovery’s Executive Editor, Bob Finn, spoke with Dr. Racke.

 

 MSDF

Dr. Racke, welcome.

Dr. Racke

Thanks.

 MSDF

So what is Kir4.1?

Dr. Racke

 

So Kir4.1 is a what’s called a potassium inward rectifying channel that’s expressed on the end-feed of astrocytes and also on oligodendrocytes. And so it’s important for trying to adjust the right concentration of potassium in and outside of a cell.

 MSDF

 

And what is its relationship to MS?

Dr. Racke

 

Well, there’s been a lot of interest recently. There was a paper published in the New England Journal now almost a year and a half ago, I believe, from Bernhard Hemmer’s group that showed that about 50% of MS patients have antibodies directed against this potassium channel, Kir4.1.

MSDF

 

And is that a lot more than people without MS?

Dr. Racke

 

Right. So when they looked at healthy individuals or looked at patients with not just neuroimmunologic diseases but also other non-inflammatory diseases, the number of antibodies directed against it was very low, on the order of magnitude of like 3%.

 MSDF

 

So what does this mean for our research in MS?

 Dr. Racke

 

You know, for a long time people have been interested in what are the potential targets, and this would represent a little bit different target than the typical myelin proteins that one has thought of as being targets in MS. It’s also kind of interesting because of another molecule, aquaporin 4, that is expressed in the same place in the astrocytic endfeet that’s been the antibody target for neuromyelitis optica. And so I think as we begin to see responses against some of these other molecules, it’s interesting to see whether they result in in demyelination and whether that can be a new avenue for therapeutic intervention.

 MSDF

 

Just within the last week, another study came to a quite different conclusions regarding the prevalence of Kir4.1 autoantibodies in MS. How do you resolve the discrepancy?

Dr. Racke

 

There was data presented yesterday to suggest that one of the differences may actually be differences in glycosylation of Kir4.1. It turns out that eukaryotes—and humans are eukaryotes obviously—glycosylate proteins, and that very often glycosylated protein looks very different to the immune system than an unglycosylated protein. And since a lot of these studies take an unusual cell type and then try to over-express to your 4.1 on its surface and then see whether an antibody recognizes it, it may not be the same type of glycosylation that’s actually seen within patients with MS.

MSDF

 

There’s a lot of research going on now on Kir4.1. What more needs to be done in this area before Kir4.1 becomes a therapeutic target?

 Dr. Racke

 

Right. Well, so, for example, if you look at neuromyelitis optica, that if you did plasmic change in those patients, then very often those patients are benefited. So it’s as though if I take away those antibodies the patient does be better, so those antibodies are pathogenic. When that’s been done in MS, the data, it’s sort of been, I don’t want to say controversial, but in some sense it is. And then there have been studies, for example, done from the Mayo Clinic that looked in at certain types of demyelinating events where it seemed like plasma exchange did work, then there were larger studies that were done and it didn’t seem to work. And if, in fact, it’s, say, a pa a patient population where really only one-third to half of the patients have the pathogenic antibody, then if I do that study and say I’m going to do it to everybody, it may not have enough power to suggest that there’s efficacy for everybody. But I think it gets back also to this idea of what a lot of people talk about in personalized medicine, right, and the idea may be that you would be able to identify patients that perhaps had an antibody to Kir4.1, and then perhaps they would be more amenable to therapeutic interventions that targeted antibody synthesis in the blood.

MSDF

 

Do you think that interventions targeted at Kir4.1, would that would it work much the same way as other as existing therapies in decreasing the number of relapses in re relapsing-remitting MS?

Dr. Racke

 

For example, if you look at things like interferon, natalizumab, the way those therapies are trying to work isn’t against the specific antigen, right. What they’re really trying to do is just interrupt the disease process. And I think the difference is going to be there have been some studies where people were trying to target the specific epitopes to either myelin basic protein – the altered peptide ligand studies were like that – and there’s studies now also where people have solubilized MHC molecule that has a myelin peptide on it. And those are specifically trying to target the immune response against a very specific antigen. Now I have to say that most of those things haven’t really worked very well, and I think part of the reason is that the human immune response is complicated enough, but by the time a person has had several attacks in MS, they probably are making an immune response against a number of myelin antigens, and so if I target just a single antigen it may not work.

And that may also end up being true in in terms of Kir4.1, that it’s just going to be another thing. But, I mean, if there’s enough similarities between it and some of the things that we’ve seen with neuromyelitis optica in aquaporin 4, like I say, there the plasma exchange and targeting the B-cell response in many instances has been quite beneficial to pa patients, right. And so I think that’s going to be an important next step to not just demonstrate that it can be part of the target that happens in multiple sclerosis, but whether inhibiting that response to that target actually has therapeutic benefit.

 

 MSDF

 

You just outlined one area of research on Kir4.1 that needs to go forward. What are some others?

Dr. Racke

The other issues have to do with trying to understand exactly the cell-type specificity in terms of glycosylation, trying to understand why is it that this particular channel is a target in MS, then are other channels also targets in MS. This sort of opens up a whole other ballgame in terms of diversity of targets that could potentially participate in MS pathogenesis.

MSDF

 

Is there anything else you’d like to add about Kir4.1 that we haven’t already talked about?

Dr. Racke

 

I’ve been in this field for 20 years, and realistically this has been the first new antigen that really has come up. And that’s sort of interesting in and of its own right. I think the other thing, obviously, for those people who are interested in things like molecular mimicry, this gives you another molecule to begin to look at in terms of its sequence homology with infectious agents. I mean, the people who are interested in, you know, viruses like HHV-6 and Epstein-Barr viruses, and those that they think that have an important role potentially in MS pathogenesis, how might infections with those agents affect Kir4.1 expression. That’s going to be another area that’ll be of interest to the research community in MS.

MSDF

 

Well, Dr. Racke, thank you very much.

 Dr. Racke

 

You’re welcome.

 [transition music]

 

Thank you for listening to Episode Four of Multiple Sclerosis Discovery. This Podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

 

 Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

 We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

 [outro music]

 

[intro music]

 

Host – Dan Keller

Hello, and welcome to Episode Three of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m your host, Dan Keller.

 

This week’s Podcast features an interview with investigators Daren Austin and Susan Van Meter of the pharmaceutical company GlaxoSmithKline, who will discuss results from the MIRROR trial of ofatumumab, a human monoclonal antibody already FDA approved for leukemia. But to begin, here’s a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org.

 

First, a complementary approach to treating MS. A new study lends support to the prevailing theory that the immune system’s ancient complement system drives persistent axon damage between MS relapses. The complement system consists of proteins that can activate innate and adaptive immune responses, but have a poorly understood role in autoimmune diseases. The new results suggest that anticomplement therapies might help prevent damage to axons. Clinical trials are in the early planning phases, but one of the study’s authors cautions that even if this approach proves valuable, it would be used in addition to and not in place of therapies targeting inflammatory T-cells.

 

In a second article, we report on a study suggesting that inhibiting a common cytokine called granulocyte macrophage colony stimulating factor – GM-CSF – might be a new therapeutic target to treat MS. Studies have shown an association between the cytokine and MS flares. A newly described class of T helper cells produce GM-CSF, and inhibiting that production might be helpful in preventing flares.

 

Finally, we’d like to call your attention to our blog series called “MS Patient, Ph.D.” There are numerous blogs and other websites where people with MS talk with other people with MS. And there are also a few, including our own MS Discovery Forum, where MS researchers and clinicians talk with other researchers and clinicians. But we can’t think of any sites where people with MS who have a scientific bent communicate directly with researchers and clinicians. That’s what MS Patient, Ph.D. is all about. It’s a place where two articulate people struggling with MS, both of them Ph.D. biologists, present their points of view about their disease and about the state of MS research. You’ll find some of their opinions provocative and controversial, and we hope you’ll join the discussion. In our two most recent posts, Griselda Zuccarino-Catania discussed the snake oil treatments touted as MS cures and relates that to the recent testimony before the U.S. Senate Committee by Dr. Mehmet Oz. And Emily Willingham discusses conflicting evidence on whether exercise is good or bad for people with MS.

 

[transition music]

 

Now, onto the interview. Here at the 2014 annual meeting of the American Academy of Neurology, we caught up with Dr. Daren Austin of GSK in London. He’s presenting the MIRROR study, which is a randomized, placebo-controlled study doing dose-ranging on ofatumumab in subjects with relapsing-remitting multiple sclerosis.

 

Interviewer – MSDF

What led you to implicate B-cells? We often think of T-cells as a target in multiple sclerosis.

 

Dr. Austin

Well, there’d been previous work using other anti-CD20 therapies in immune inflammation diseases that have shown efficacy. Most notably the first was rituximab in rheumatoid arthritis and subsequently rheumatoid looking at multiple sclerosis, so the precedence for anti-CD20 modulation as a target for inflammatory diseases was known before we came to design this study. What wasn’t known before we designed the MIRROR study was how much modulation of B-cells would generate what level of clinical benefit. The primary objective of this study really was to look at how best we could administer ofatumumab, which is an anti-CD20 monoclonal antibody, to modulate B-cells and then modulate clinical disease.

 

MSDF

How’d you go about it? Can you describe the study and also what you found?

 

Dr. Austin

Well, the study was a randomized, double-blind, parallel group study looking at relapsing-remitting multiple sclerosis patients who had to have evidence of disease activity, i.e., they they would be requiring therapy. What we did was we took what we knew about the pharmacology of ofatumumab – and we’d previously conducted both an intravenous study in in multiple sclerosis patients, so we knew the drug could be efficacious in suppressing MRI lesions, and we took what we knew about the clinical pharmacology of ofatumumab; and, namely, that it is an extremely potent depleter of B-cells. We began by by hypothesizing that there was a link between the level of B-cell suppression and the level of MRI lesion suppression. From that we produced some some predictions. And our predictions led us to suggest that extremely low doses given relatively infrequently could be beneficial. We produced a transimulation before we conducted the trial, and we proposed a range of doses and dosing frequencies. So the first dose level was was placebo, the next level was a 3 mg dose that was given once every 12 weeks. The next dose level was 30 mg given once every 12 weeks. The next dose level was 60 mg given once every 12 weeks. And, finally, because we knew that a dose of 200 mg was efficacious over 12 weeks, we gave 60 mg every 4 weeks to give a cumulative dose of 180 mg. So we explored a dose range, a cumulative dose range, of 3 mg to 180 mg, with the primary endpoint being evaluation of MRI lesions at 12 weeks. Placebo patients were then given a 3 mg active dose. All patients were then followed for a further 12 weeks, and we now have the 24-week data. And, again, treatment then ceased and patients were followed-up to see repletion of B-cells.

 

And what we found in the study was, yes, that ofatumumab is is extremely potent at depleting B-cells. That single 3 mg dose was capable of knocking out about 75% of circulating B-cells, and the 60 mg dose given every 4 weeks depleted almost all patients right down to the undetectable levels, which is had been seen in the past. What we were able to do then is to look at the dose response to dosing of ofatumumab at the 12-week endpoint, and what we found is that at the cumulative dose of 180 mg, we see over 90% suppression of lesions. But we found that there was no incremental benefit in going above doses of about 60 mg, and in fact the dose that generated the half maximum effect from an analysis of the data was predicted to be less than 3 mg; a single 3 mg dose generated half of the maximum benefit.

 

Having shown that we have got clinical suppression of MRI lesions, we then decided to relay the pharmacology of ofatumumab, which is suppression of B-cells, to the clinical benefit, which is suppression of MRI lesions. And that was the purpose of this abstract, that the analysis that we presented showed quite clearly that there was a very strong relationship between how much you suppress B-cells and how much you suppress MRI lesions. But the surprising thing from this data is that you don’t have to fully deplete all patients to below the limit of quantification to derive benefit. We showed using a variety of analyses that patients that have circulating B-cells of less than 32 to 64 cells per microliter on average over the course of the dosing interval would still derive maximal benefit, i.e., suppression of lesions, to 90%. And that’s intriguing. And the reason it’s intriguing is that the doses that we gave are only acting on peripheral B-cells. There’s been speculation as to where the drug needs to get to give clinical benefit, and that the doses that we give – up to 60 mg doses – the drug can’t penetrate the blood-brain barrier. And, therefore, we know that by modulating peripheral circulating B-cells, we are deriving the maximal benefit in suppression of MRI lesions.

 

MSDF

Is the drug acting on mature B-cells, or in B-cell development which may then migrate into the CNS during development?

 

Dr. Austin

So ofatumumab only binds to the cells that express CD20, so there is some consideration as to where those cells exist. Now it is entirely possible that immature cells maybe sort of enter the periphery not expressing CD20, move to across the blood-brain barrier where they subsequently develop. That is a possibility. And if that is the case, our drug is not capable of reaching those B-cells. Only cells that express CD20 are depleted, so plasmablasts, for example, are not depleted because they do not express CD20. It is just that that population of of of B-cells that are expressing CD20. There’s a lot of hypotheses about how B-cells are working, how they may be producing pathogenic antibodies that may be detrimental. In MS it could be anti-myelin antibodies, for example. But we don’t absolutely know that that is the sole pathogenic mechanism in MS, as in other diseases. It may well be that B-cells are modulating other, say, T-cell activity, which we do not yet know. What we do know from our trial is that modulation of peripheral B-cells gives you benefit, and that’s the principal finding, and that the doses that we modulate at are much, much lower than the oncology doses that have previously been given.

 

MSDF

So you don’t yet know whether you have a direct antibody effect on B-cells, or whether it’s acting possibly through antibody-dependent cellular cytotoxicity.

 

Dr. Austin

We do know that the mechanism of B-cell depletion is through both ADCC and complement-dependent cytotoxicity. That is the primary pharmacology of ofatumumab on cells that express CD20. We do not and cannot say for certain what those B-cells were doing prior to being depleted and how they were driving the pathogenic process, but we have shown that by depleting them to levels of less than 32 cells per microliter, you see suppression of disease activity. One of the important things to say is that the regimens at the every 12-week dosing that we’d selected, there is some evidence that B-cells do start to grow back in at least half of patients, so dosing every 12 weeks pre-dose, there are some circulating B-cells. If we look at immature B-cells, there are lots of immature B-cells but they haven’t yet moved to the to express CD20. So what we see is that the regimens we’ve designed, there is some evidence of of repletion, i.e., that patients are seeing clinical benefit despite having circulating B-cells.

 

MSDF

How does this fit in with the pathogenetic mechanisms of T-cells? Are there interactions in the pathologic process besides the regulatory effect of T-cells themselves?

 

Dr. Austin

The truth is I don’t think we can say. All we can say is that modulation of B-cells circulating in the periphery gives clinical suppression of of MRI lesions, and by implication we believe at the clinical efficacy in multiple sclerosis, and possibly other diseases, although such low doses have not have yet to be tested in other diseases.

 

MSDF

In terms of B-cell repletion, have you also followed new lesions after B-cells come back?

 

Dr. Austin

We have the 24-week data and we have preliminary data out to 48 weeks, and that data won’t be reported yet because we’re still in the process of ana analyzing it. But in the trial we designed, we had individual follow-up to watch patients B-cell replete back up to the lower limit of normal or their baseline, and we are measuring their follow on MRI lesions.

 

MSDF

Working along with Dr. Austin on this project is Dr. Susan Van Meter, the clinical physician involved in the project. Let me ask you, what sort of adverse effects did you see during the trial?

 

Dr. Van Meter

The most common adverse effect that we saw was injection site reactions, and that can include things such as redness at the injection site, nausea, flu-like symptoms. That occurred in most of the patients receiving ofatumumab. It also, very interestingly, occurred in about 15% of patients who received placebo.

 

MSDF

In terms of the more serious and chronic effects, did you see any opportunistic infections or especially progressive multifocal leukoencephalopathy?

 

Dr. Van Meter

So you would certainly worry about infections, especially serious infections. We did not see any cases of PML or other opportunistic infections, and, in fact, no serious infections. As typical for patients with MS, patients did have a variety of infections – urinary tract infections, respiratory infections – but this was seen in all patients including placebo patients, and there was really no evidence of an increased rate of infection in patients receiving ofatumumab.

 

MSDF

What do you see as the potential clinical significance of these findings?

 

Dr. Van Meter

Well, I think it offers another therapy option for patients with MS. Obviously, we have to do further development and show that the benefits that we saw on MRI translate into clinical benefit on relapse rates and disability progression. But we’re offering a subcutaneous dose as opposed to an intravenous dose of medication, and potentially offering a medication that doesn’t completely wipe out one part of your immune system.

 

MSDF

Is there a reason for selecting ofatumumab over rituximab?

 

Dr. Van Meter

Well, I think that would be a clinician choice, to be honest. Rituximab has certainly been studied for multiple sclerosis even though it’s not indicated for multiple sclerosis. There’s another B-cell therapy that will be on the market when we launch, ocrelizumab, and I think it will come down to physician and patient choice.

 

MSDF

Is there anything we’ve missed or that’s important to add?

 

Dr. Van Meter

Well, I think at Glaxo we are very excited about this data; this is new science. Obviously, we need to understand more about it, replicate it. But for the first time, we’ve shown that you don’t need to completely destroy all the B-cells to have effect in multiple sclerosis.

 

MSDF

Very good, I appreciate it. Thank you.

 

[transition music]

 

Thank you for listening to Episode Three of Multiple Sclerosis Discovery. This Podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

[outro music]

Transcript of Episode 2 with Dr. Barbara Koppel

 

[intro music]

Host – Dan Keller 

Hello, and welcome to Episode Two of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m your host, Dan Keller. 

This week’s Podcast features an interview with Dr. Barbara Koppel, whose recent review of published studies concluded that certain forms of medical cannabis can be helpful in treating some symptoms of multiple sclerosis. But first, here is a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org. 

First, predicting MS risk. Cardiologists can use the Framingham risk assessment tool to predict the likelihood that one of their patients will develop heart disease. But what about MS? Given that researchers have now found 110 genes related to MS risk, are we close to a formula that can predict who will develop MS and what course it will take? Disappointingly, the answer is probably not. Reporter Emily Willingham writes that “Decoding MS risk factors is less like fitting together a jigsaw puzzle and more like balancing a Jenga tower, with layer upon layer of complex interactions and unpredictable outcomes if something changes.” For those of you who may not be familiar with Jenga, it’s a children’s game popular around the world that involves balancing wooden blocks in the form of a tall tower; our article includes a helpful photo. 

Next, what does the nose know about MS? Maybe a lot. Many people with MS lose their sense of smell, and now a new study involving postmortem brain samples appears to show that, contrary to earlier studies, the olfactory system is the site of significant demyelination and axonal loss. Could it be that the olfactory system is an important link between environmental exposures and MS? Stay tuned. 

Finally, we’ve just posted our newest data visualization. This one is a scientific literature treemap that makes it easy to zoom in on peer-reviewed articles or clinical trial listings describing randomized, double-blind MS trials. Our own extensively researched drug development pipeline provided the source material for this visualization. 

[transition music]

Now, onto the interview. Dr. Barbara Koppel is Chief of Neurology at Metropolitan Hospital in New York and Professor of Clinical Neurology at New York Medical College. Along with Dr. Gary Gronseth of the University of Kansas School of Medicine, she conducted a systematic review of the literature on treating MS and other neurological diseases with medical marijuana. I caught up with Dr. Koppel at the annual meeting of the American Academy of Neurology in Philadelphia.

MSDF

First of all, let me ask you why do you use the term marijuana? Most people around the world use cannabis? 

Dr. Koppel 

There is a difference, there’s a technical difference. Cannabis, I think, only refers to some of the derivatives, and we thought medical marijuana, more people would connect with that, they would know what we were talking about; the current buzzword, but it also refers to both pills and smoked and everything else. 

 MSDF 

And what did you look at in review, what forms of medical marijuana or compounds?

Dr. Koppel 

The reviews went back to studies since 1948, and the compounds that were used were pills, an oral mucosal spray that’s called nabiximols that I’d never heard of but it’s used in England, and then a few of the studies covered smoked marijuana which were marijuana cigarettes basically.

MSDF 

And what did you find, specifically the use of it for multiple sclerosis?

Dr. Koppel 

There is symptoms that it helped. It was most efficacious in spasticity, in reducing spasticity – more on the patient-related scales than the doctor Ashforth scale – but in depending on which study we looked at, the pills helped and the spray would help. It was also useful in reducing pain levels, either pain from spasms or pain from central causes – you know, burning numbness type of pain – and it reduced the number of voids, bladder voids, but some of the other bladder symptoms it had no effect on. It didn’t help tremor, which is also good to know because now we have to keep looking for other things for tremor in MS. Then we looked at other diseases, but most of the work has been done in MS.

MSDF 

Right now in the US there’s only one form, a pill form, approved. Do you think that you had sufficient data to make any conclusions or recommendations?

Dr. Koppel 

The pill forms that are available here, they’re not approved for anything other than chemotherapy-induced nausea and appetite in AIDS patients, so they were used in some of the studies and they were useful for spasticity, again, and painful spasms. The problem is that the pills are primarily THC rather than cannabinoid, so it’s hard to get up to a dose that’s working without the toxicity that comes along with THC; they they weren’t all that great. The one study using smoked marijuana was in the US, and they used marijuana cigarettes which trended towards efficacy, but the study didn’t have enough power to make any conclusions from; there weren’t enough patients basically.

MSDF 

Is the oral spray – which isn’t available in the US – a different composition, and does it have any differences in effect or advantages?

Dr. Koppel 

It has a big advantage because it’s a combination of cannabinoid – which is the part of the cannabis that you want to reduce symptoms – and THC. And the psychoactive side effects usually come from the THC as opposed to the cannabinoid, although it does have some psychoactivity as well. So the main advantages that I could find is that patients could self-titrate; they could use up to a certain numbers of pumps a day. But if they felt better with two or three pumps, they could stay at that dose. If it didn’t work at that dose, they could go up to six or seven – I forgot – the maximum. So I think that was found to be more effective, just because patients could take a dose that was adequate. It is going to be studied here, it’s the company has got testing sites mostly for epilepsy now, but it will become available here.

MSDF 

Have you found either in practice or from any studies whether patients were reporting self-medicating, especially with smoked form?

Dr. Koppel 

Yeah. The We couldn’t use those studies to make this systematic review because no one really examined them and they’re just basically testimonials or questionnaires, but there was a lot of literature that included that. And, in fact, one of the earlier papers from England, that’s why they began looking at more suitable forms of cannabis, because their patients were self-medicating by smoking, you know, just regular old marijuana and reporting that to their doctors, and and then the doctors tried to translate that into a pill form or a spray form that could be looked at more rigorously. And my patients in New York, you know, they they’re not shy. I don’t have a big MS practice, so my patients are more likely to be seizure patients. It’s not that they use it for their seizures. Every once in a while they’ll ask me if it’s okay, if it’s going to cause seizures or withdrawal, like alcohol withdrawal can cause seizures. And I can now tell them, no, it’s safe enough from that point of view.

MSDF 

I think you had mentioned in a news conference that there were 2 out of something like 623 patients who had did have seizure that might be attributed to use of the drug, so I take it that does not concern you. Are those small numbers, especially since you’re dealing with patients with epilepsy?

Dr. Koppel 

Yeah, those are small numbers. And what I’ve found is that they used to say patients with MS didn’t get seizures, but they do. There were actually four seizures that were reported, and two they didn’t blame on the drug; so they were either in the placebo group or they were patients that already had seizures. But it’s always something to worry about, but it’s such a small number that I wasn’t concerned.

MSDF 

While we’re on the subject, what other adverse effects did the studies you reviewed note?

Dr. Koppel 

The common ones that appeared in at least two two papers were things like nausea, fatigue, dizziness, fainting. In some of the studies that used the more potent forms that had more THC, they had hallucinations and depression and suicidal thoughts, but no one actually did commit suicide during the studies.

MSDF 

Is this a problem in MS since some of these types of symptoms or problems occur with the disease itself, could these be exacerbating it or are they directly related, do you think, to use of the drug?

Dr. Koppel 

That makes it complicated and that’s why you need kind of rigorous studies so that you can compare dose effects and things like that. But if a patient already has cognitive impairment, they may have trouble dealing with the side effects that, you know, that I mentioned. It’s easy to confuse that issue with the heavy users, the recreational users who end up with cognitive impairment that can be permanent. These were doses that were nothing like what people use for fun.

MSDF 

If this works out that it would be a useful form of drug if testing shows validity, who do you see it being recommended for? People refractory to certain other medications, or how would it be used?

Dr. Koppel 

That was the case with all the studies, they were allowed to try everything there was up to that point and kind of added this marijuana as a last-ditch effort. So I would say if a patient’s got uncontrolled spasticity or too much pain, they should try it. I wouldn’t really recommend it for bladder issues because it wasn’t that successful, and I definitely wouldn’t recommend it if tremor was the symptom they were trying to get rid of. So it just depends on what the patient’s telling you is bothering them the most. And, obviously, the patient has to be willing to assume all the side effects. I think one of the good things about this is some of the stigma is possibly going away so that… There’s a lot of people who assume that patients that want to try it, it’s just because they want an excuse to, you know, use recreational marijuana and get high, and it it really wasn’t the case in the studies.

MSDF 

It seems like it’s long past due to be rigorously testing these things.

Dr. Koppel 

Yes, I I agree. It has been tested in other disease states, this is just a piece of the pie where marijuana is used. It’s been used on patients with intractable pain from cancer or people with glaucoma have benefited from it; there’s usage out there. And the states that have legalized it, they don’t care which condition it’s being prescribed for. So I think it’s just neurology’s kind of lagged behind because it’s been so hard to do research on it in this country. Even in England where a lot of the studies were done, they put into their reports that it wasn’t easy to get approval. It’s not legal there either, but I guess they just were more persistent in studying it. 

MSDF 

Since in most of the studies that you reviewed, it was used sort of as a last resort or an add-on later, would you see that as its primary role or could it take a more prominent role?

Dr. Koppel 

As I said, I usually treat seizures, and what I try to do is not pile on one pill after another pill. If something seems to work, I’ll take away something that wasn’t working. So I think that’s the role for it, because if you take everything you’re going to definitely accumulate the side effects and then you really have trouble functioning. So I think if this works better than some of the existing treatments, there’s no reason to take both of them. Let me just add, it still shouldn’t be your first-line treatment, you you should still try the traditional ones first. And mon many of these trials only lasted 8 weeks; you don’t need forever to decide if something’s helping or not.

MSDF 

What would be the message to physicians who contemplate advising patients about medical marijuana?

Dr. Koppel 

I can’t tell them to go ahead and prescribe it because – for two reasons – I don’t really love the form that’s available here because it’s all THC, and it’s not FDA-approved for these conditions, so they’re still taking a chance on breaking that rule. I would advise physicians to find trials or to do a trial rather than just tell patients… even in the states where a doctor can give a card that says they agree with using medical marijuana, you you lose control of the dose and how much how much the patient smokes, and all that. So I would encourage some more traditional pills and sprays to be studied so that then they could be prescribed.

MSDF 

Should these prescriptions, or recommendations, really come with either informal or formal informed consent about side effects and possible things to avoid doing, like driving?

Dr. Koppel 

We should probably do that on a lot more pills that we’re currently prescribing. I I don’t always routinely do it, but the pharmacy tends to hand out a list of dos and don’ts, and some of the bottles are labeled don’t drive. It’s not that different from other CNS-depressing drugs, but it’s worth warning people. And, actually, I think it shows up in their urine, so if they’re going to go somewhere where a tox screen might get done, they they should have a card or a prescription that shows that it was prescribed.

MSDF 

This systematic review is being published in the Journal of Neurology on April 29th, and also, I guess, it’s already been endorsed by certain societies, medical societies?

Dr. Koppel 

They sent a summary of the findings to, I guess, other other societies that deal with the same conditions, because in addition to MS, we studied Parkinson’s and Huntington’s and Tourette’s and seizures, even though there were only two studies for that. So some of the other societies have not confirmed it but endorsed it in the sense that they agree with what we found.

MSDF 

I appreciate it.

[transition music]

Thank you for listening to Episode Two of Multiple Sclerosis Discovery. This Podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. 

 

Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 

[outro music]

 

 

 

 

 

Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum

Transcript of Episode 1 with Dr. Timothy Vollmer

[intro music]

Host – Dan Keller

Hello, and welcome to Episode One of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s Podcast features an interview with Dr. Timothy Vollmer, who discusses strategies for maximizing brain health in people with MS. But first, here is a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org.

First, oral contraceptives. According to a retrospective study published in the journal Fertility and Sterility, women with relapsing remitting MS who used combined oral contraceptives tended to have less severe disease, and they were less likely to move on to secondary progressive MS. On the other hand, this study showed no association between oral contraceptives and annualized relapse rates or EDSS scores. An intriguing set of associations, but correlation does not imply causation.

Next, the blood brain barrier. A study in PLOS ONE showed that when cultured blood-brain barrier cells are treated with serum from MS patients the cells decrease their production of tight junction molecules and increase their production of cell adhesion molecules that promote cell migration. Breakdown of the blood-brain barrier is an early feature of MS, and this allows activated leukocytes to migrate into the brain. Understanding this process is important in its own right, but the study also raises questions about the safety of blood donations from people with MS. Does this study suggest that people with MS should be barred from donating blood? Let us know your opinion in the comments.

Finally, we hope you’ll check out our new data visualization section, which will allow you to see MS-related data in new ways. Our first visualization is a bubble chart presenting data from 106 MS clinical trials published between 1986 and April 2014 involving 44,606 patients. You can easily sort the data by compound, by trial phase, by dose, by year, by funding, or by population. Please let us know if you discover something unexpected or particularly striking in the data.

[transition music]

Now, onto the interview. Dr. Timothy Vollmer is a practicing neurologist specializing in MS. He’s also professor and director of clinical research at the University of Colorado Denver. Bob Finn, our executive editor, caught up with Dr. Vollmer at the annual meeting of the American Academy of Neurology in Denver.

Interviewer – Bob Finn

This is Bob Finn from the MS Discovery Forum. I'm here with Dr. Timothy Vollmer of the University of Colorado Denver Rocky Mountain MS Center, who among other things is interested in how to maximize lifelong brain health in people with MS. Dr. Vollmer, welcome.

Interviewee – Timothy Vollmer

Thank you.

MSDF

Why is now a good time to ask about maximizing brain health?

Dr. Vollmer

Well two reasons: one is because recent research has indicated that there are both medical ways and lifestyle ways to actually improve brain health, and the the data suggests that if we do that that's going to improve people's function later in life and allow them to be the grandparents that they want to be or other things that they want to do later in life. And the second reason is is that we now have nine FDA approved therapies to alter the course of MS by inhibiting the inflammation that causes the damage in the brain. And our challenge is figuring out how to use those most effectively.

MSDF

So how do you measure a concept as broad as brain health?

Dr. Vollmer

The easiest measure is actually the size of the brain. One of the unfortunate consequences of multiple sclerosis – as is true with hypertension, cardiovascular disease, strokes, dementia, and other things – is that neurons are dying. So MS is not just a disease of myelin; it's a disease of the entire brain, and it affects neurons and cells called astrocytes and cells called oligodendrocytes that make up the bulk of what the brain is. The result of of loss of these neurons is the brain has less and less flexibility in terms of shifting function around from areas that are not working well to areas that are working well. That ability to switch, or shift function around, is something that we do automatically throughout life. Every time we bump our head and get a little bit of bruising in the brain the brain can compensate by shifting function around. This is the same issue that the NFL is dealing with with its football players and mothers are worried about with their kids in contact sports. The problem of multiple sclerosis is that most of the disease activity is actually below the radar – it's not presenting as relapses – and you don't see it unless you're doing regular MRIs, or you're doing a a more modern MRI technique called a volumetric MRI where you can actually measure the three-dimensional volume of the brain. And we do that routinely in studies, and we know that in MS the brain is shrinking at a rate of about six times faster than the normal healthy controls. That's the fundamental problem in terms of maximizing lifelong activity is we're losing brain function too fast in the early phase of the disease.

MSDF

So how does this concept help guide treatment?

Dr. Vollmer

Well it turns out that there actually are three components to a treatment plan that wants to maximize brain health over a lifetime. The first one in multiple sclerosis is obviously to try to prevent further damage to the brain by using the immunological therapies that we have in the most effective way possible. And that's a a bit challenging, but the fact is we have a lot of opportunities now that we've never had before. And this is an issue for the medical field. The second aspect is it turns out that more and more research – including that presented here at the American Academy of Neurology meeting – suggests that if you exercise and are intellectually and physically active that increases your brain reserve. It does that because as you fire neurons by doing something – learning a language, volunteering, going to church, reading, whatever – that causes the nerve cells to put out new branches called neurites. And those neurites randomly connect with other neurons in the vicinity. If you do something to activate that pathway, then you make it permanent. If you don't do something to activate that pathway, it breaks automatically within 24 to 48 hours. So you need to be active on a daily basis really to try to maximize those connections. And what you're doing you're just creating this three-dimensional network of connections between nerve cells that gives the brain the flexibility of shifting function around. And it was reported at this meeting – and it's been reported in the literature a number of times – that people who are intellectually active actually have less disability controlling for all other factors than people who are not intellectually active. And we now know that that's also true by being physically active. And again, this cuts across multiple diseases, but it's just as important in MS as it is in other ones. And then, the third factor is diet. The reason for that is not that there's a specific MS diet; there isn't. But we know that if you develop other dietary related diseases, that substantially increases your risk of disability from MS. So for example, just developing diabetes almost doubles your risk of being disabled from MS than just having MS alone. So just having high blood pressure, just being overweight or obese increases your risk of disability. So that means if we want to maximize lifelong outcomes then we prevent injury by using the drugs as effectively as we can; we get people to exercise and be intellectually active to create more connections with brain, create more cognitive and brain reserve; and we also help them develop a healthy lifestyle from a nutrition aspect, as well, to prevent them from developing other diseases that would compromise neurological health. 

MSDF

Well all of this sounds interesting, but it sounds completely obvious to me. What is controversial about this subject?

Dr. Vollmer

There are two things. One is that the medical profession is just now beginning to evolve in the direction of trying to think about global health and chronic diseases. Primary care physicians have been thinking about this for some time, in general, but in terms of applying it to chronic diseases this is a a relatively new concept, and how to do it is still a challenge. The second reason is that regulatory agencies, in other countries, and then in this country, health insurance organizations, prevent us from doing this. So for example, in early phase disease for patients who don't carry a virus called JC virus, a drug called natalizumab or a drug called fingolimod might be actually be the best drugs for them. But the insurance companies, even Medicare and Medicaid, make it very difficult for us to use them in the patients. They tend to approve the old drugs first because they perceive them as cheaper usually through sweetheart deals made by the private insurance companies or just because of concerns of cost on the part of Medicaid. And they prevent us from using more effective drugs earlier; they don't understand this concept of preserving brain volume and brain health in terms of trying to maximize lifelong outcomes.

MSDF

Is there any proof though that starting with fingolimod or natalizumab – starting with the "heavy hitters" – will prevent the the long, slow progression?

Dr. Vollmer

Yes and no. The problem is the gold standard would be a 50-year study looking at 10,000 people. That's never going to be done partly because the target is constantly moving as new therapies come into the marketplace, but also it's just not practical. However, having said that, published both in the peer reviewed literature and at the American Academy of Neurology meeting are a number of relatively large studies done at centers around the world – most not funded by drug companies – that have reported that patients on fingolimod or natalizumab are significantly better off after two years of treatment than patients using interferons or glatiramer acetate. And at this meeting, specifically they compared in an open-label way patients who were started on fingolimod versus patients started on interferons or GA or switched, and again they showed a 50% reduction in relapse rate. And in the literature for natalizumab, there have been reports since 2010 of the fact that if you're treating relapsing MS patients over two years period of time, on average, that group is improving in function. And that includes fatigue, cognition, mobility, employability. So with highly effective therapies, we do have evidence, substantial evidence, that slowing down brain volume is important, and that results in better function and often resolution of symptoms – patients actually get better on these highly effective therapies. And we've not seen that with interferons and glatiramer in most patients.

MSDF

As a physician, can you recommend strategies for making the argument to third party payers?

Dr. Vollmer

Yes. There is a lot of research data that proves that brain volume or gray matter volumes or the number of neurons that you have in your brain is the most powerful predictor of what's going to happen to you in terms of disability over your lifetime, and this is not an arguable point. However, regulators tend to look at relapse rate reduction and gadolinium-enhancing MRI lesion reduction, which are not very good at predicting long-term outcomes. So we need to reeducate health insurers and third-party payers that if you really want to optimize patients' lifelong health you need to make the investment upfront in highly effective therapies to prevent them from developing more disability. We know there are a number of studies reporting that total healthcare costs are less if you're using highly effective therapy like natalizumab or fingolimod over time than they are with interferon and and glatiramer acetate. So this has been published in many different ways; there's more than a dozen papers in the literature on this. The problem is is that any one study is relatively small, and it's easy to criticize it. But the field needs to step back and look at the overall literature. And the overall literature is consistent; we consistently demonstrate that if there's an effect the effect is in favor of using more effective therapies as early as possible in the disease course. 

MSDF

Aside from brain volumetrics, what are what are some other good ways of measuring brain health?

Dr. Vollmer

Well you can look at the number of what are called T2 lesions that are developing on the MRI; so your neurologist can look at that, and they can compare you to other patients of a similar age and try to determine are you on the good end of the spectrum or or the more worse end of the spectrum. You can look at what's called T1 black holes; it's a typical MRI measure that's always done. But T1 black holes are more correlated with worse long-term outcomes, and so if you have more T1 black holes you really should be thinking about being on a more effective therapy. And certainly, if somebody is on a therapy and they continue to have any evidence of disease activity – which means a relapse, a change in the MRI or progressive disability – they should probably be thinking about being on a more effective therapy, and they should be discussing that with their physician. 

MSDF

I'm a little surprised that you didn't mention any cognitive measures.

Dr. Vollmer

It’s only because I assume automatically that they're very important, and, in fact, most of the data on brain reserve is focused on cognitive function. However, I would argue that the same principles apply for mobility, for sensation, for vision, for creativity. And so, MS is a disease of the central nervous system, so it attacks the very core of what it is to be human. We tend to focus on the bipedal nature of human behavior, but that's not the most important thing. The most important thing is maintaining your interaction with your family, with your friends, with your profession, being able to progress and learn, etc. We can deal with mobility issues, but we don't have a way to recover cognitive function yet.

MSDF

Are you yourself conducting any studies in this area?

Dr. Vollmer

Yes. We have a number of studies; we actually have 28 clinical studies going on in MS. But two of the ones that I think are very relevant to this particular issue is we have been funded to be able to look at the changes on MRI in patients that have been on either fingolimod or natalizumab for two years or longer. And we're comparing them to age matched healthy controls. And what we're asking is is the rate of brain volume change, which all of us suffer, but is the rate of that change in those patients now similar to what it is in healthy controls versus patients who have MS? And as I said, we know that the percent change in brain volume for healthy people is about 0.1% per year; in MS it averages about 0.6% per year. So we're we're doing this study now to see the patients who are doing well – they're coming into the clinic, they're saying I'm feeling good, I feel like I'm as good or better than I was last year – is their brain now normalized in terms of its very modest loss of brain volume over time as a result of normal aging? 

MSDF

And you said there was a second one that that is particularly relevant.

Dr. Vollmer

The second one is is to take and ask patients, it's called patient reported outcomes – where we actually ask the patient about how they're doing in cognition, how they're doing with energy, how they're doing with mobility, how they're doing with sexual function, you know, the things that are important to us – and we're asking how that is changing over time on these therapies, and we're trying to correlate that back with what's happening to their brain MRI in terms of brain volume. 

MSDF

Dr. Vollmer, I've come to the end of my prepared questions. Is there anything else you'd like to add or any questions I didn't ask that I should have asked?

Dr. Vollmer

Two things. As I said, one is it's very important for patients and the healthcare profession to really begin to understand that MS is a disease of the entire central nervous system, and its impact on neurons is actually the most important aspect of this of this disease. The second one is that healthcare providers working with MS patients and MS patients and families need to advocate to the healthcare system to allow healthcare providers to use the most effective therapy that works best for that patient based on individual assessments of safety and efficacy. 

MSDF

Well thank you very much.

Dr. Vollmer

Thank you. Appreciate the interest. 

[transition music]

Host – Dan Keller

Well that’s it for Episode One of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum—MSDF--the premier source of independent news and information on MS research, Robert Finn, executive editor. MSDF is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is the Vice President of Scientific Operations. 

MSDiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

 [outro music]