[intro music]

Host – Dan Keller

Hello, and welcome to Episode Seventy-five of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.

Today's interview features Elaine Kingwell, a research associate at the University of British Columbia in Canada. She and her colleagues have gathered and recently published incidence and prevalence figures for people with MS in the province. I spoke with Dr. Kingwell at the ECTRIMS meeting in Barcelona in October to find out the reason for the study and to explore the changing trends she found and their significance.

Interviewer – Dan Keller

What prompted you to do this study?

Interviewee – Elaine Kingwell

In British Columbia, we know that Canada has got a high incidence and prevalence rate of MS, but we don't actually have the numbers, so we've been doing a lot of research on MS in British Columbia for many, many years. But we don't have the incidence numbers for BC, and also the prevalence is out of date – the estimates that we have – so it really was time to get an idea on how many people we have in BC. And also, we wanted to look at change over time, and we have access to some amazing administrative databases in BC and also had some algorithms that we could use that have been validated, so that we could identify people with MS in the databases.

MSDF

Why are these numbers important?

Dr. Kingwell

It's important for lots of different reasons. For instance, it's important to monitor trends over time. We're able to do that in BC, because we have data going back several years. And so, it's important to see if populations are changing, so that we can get some clues about whether environmental factors might be changing. And also, for the prevalence estimates, it's important to know how many people have MS in the province, so that healthcare planning can be done wisely and resources.

MSDF

How do you go about looking at this?

Dr. Kingwell

So as I mentioned, we did use the health administrative databases in BC, which are big databases that collect data on the whole population. A number of different databases were combined, including hospital admissions and physician visits. It's all claims data, so that when someone goes to see their physician, a billing claim gets put in with their diagnosis. So we use these codes to identify people with MS. And we basically estimated the number of people with MS [over] several years – one year at a time – so that we could look at change over time for prevalence. And we also estimated the incidence, the number of new cases each year, starting in '96 right up until 2008.

MSDF

What did you find in terms of incidence and prevalence?

Dr. Kingwell

Well we found the incidence and prevalence are both high. The incidence was around 7.8 per 100,000 per year, and the prevalence was around 180 to 200 per 100,000 in 2008. So they were both high, what is relatively high compared to other places in the world and similar to rates that have been found in Europe, in Northern Europe, and other parts of Canada, as well.

MSDF

And the prevalence is increasing over time?

Dr. Kingwell

Yeah, we found that it increased quite significantly by about 4.7% per year, so a big increase. It also shifted in the predominant age of people, so that the peak prevalence age was around in the mid-40s in the 1990s, and it's now shifted up into the mid-50s. So the population of people with MS is getting older in BC. We also saw with incidence … quite differently, the incidence was not changing over time, so it stayed relatively stable; it did fluctuate as incidence always does. But over time, on average, it stayed the same.

MSDF

Are those two pieces combined—increasing prevalence and older age—good news?

Dr. Kingwell

I don't know if any of it's good news. It means that we have an older population that are probably requiring more care, as they get older, for the MS, as well as, of course, comorbidities they may have. So, it's certainly something that healthcare planners need to be aware of. And we have an aging population, in general, in Canada, as we do in other parts of the world, but we have a lot more people with MS at an older age.

MSDF

But doesn't that mean they're surviving longer?

Dr. Kingwell

That's the good news part, yeah. And it does mean that, because we're not seeing a change in incidence, the most likely explanation is that the survival is better. People are surviving longer with MS. We're seeing an increase in survival for the whole population, but we're also seeing an increase in survival for people with MS.

MSDF

What about the gender ratio in terms of prevalence but also in terms of survival?

Dr. Kingwell

We're seeing a gradual increase in the number of women relative to men in prevalence. That's most likely due to the fact that women do survive longer than men, on average, of course that's highly variable. But on average, they survive longer than men. And so, if you've got an aging population and three-quarters of the people with MS are women, then you're going to find the number of women are increasing.

MSDF

How did the socioeconomic status affect the findings?

Dr. Kingwell

Yeah, so we did actually look at socioeconomic status. It was measured at the neighborhood level, so not the individual level. It's linked into the databases by postal code. We did find that there were more people with MS in the higher levels of socioeconomic status, but the absolute differences were not that great. And, when we looked at this, it was not linked or adjusted for other factors. So there's so many things that can be attached to socioeconomic status and, of course, age is one of them, and your age is greatly related to whether you have MS or not. And so, there are other possible explanations, so we don't put a lot of emphasis on that. When we look at socioeconomic status, we really think that you need to design a study specifically to look at that.

MSDF

Could you look at the use of disease-modifying drugs according to socioeconomic status?

Dr. Kingwell

We could, and we have actually looked at that in other studies. Again, as a kind of an adjustment factor or something to bear in mind when we're looking at lots of variables at once, we find there's the same kind of trend that people in the higher levels tend to be on drug more often. But again, the absolute numbers are very small, and it could totally be related to age or other factors that are not adjusted in.

MSDF

Were the data there to be able to look at early initiation of disease-modifying drugs and any effects it may have had?

Dr. Kingwell

Well for this particular study – in the incidence and prevalence study – we looked at just whether people had ever had drug. We looked at the incident population to see if they'd had it in the last three years or so—that's the three years from their first claim, which is close to when they're first diagnosed or recognized as having MS. And for the prevalent population, we looked at whether they'd ever had MS. So we were able to tell that about a third of the cases had had a disease-modifying drug. And this study did start way back in the early 90s and then mid-90s for the incidence cases. So, you would expect it to be a lower rate because the drugs were just starting to become available in the mid-90s. So we didn't look at the actual start date of the drug for this particular study; we certainly are able to look at that because we have access to the databases to look at those kinds of questions, and we are looking at those kinds of questions in other studies.

MSDF

Can you put your findings in context to other studies at other latitudes, locals, healthcare systems?

Dr. Kingwell

Yeah, that's a complicated question. Certainly as studies are similar to the findings from some other studies. In particular, in Canada, there's been some very similar studies done in Manitoba and Nova Scotia where we've used exactly the same algorithm that was validated in those provinces led by Dr. Ruth Ann Marrie from the University of Manitoba. So, we found that prevalence and incidence estimates are very similar, and the findings and the change over time are also very comparable. When we look at some of the other countries, there are some similar findings in other places, but they vary a lot. When it comes to latitude, of course, we didn't have a big latitude gradient in our study; we were just looking in BC, and most of the people in BC live in one area around they're concentrated in the south of the province. But certainly there's a lot of variation in findings. But in order to get a look at the change over time, you really need to look within the same population on more than one occasion rather than comparing between populations over time. It's really difficult to make that comparison.

MSDF

Do you have a particularly good situation in BC in that you can link databases of diagnostic codes, physician visits, hospitalizations, pharmacy benefits, things like that that may not exist in other places with a less coordinated system?

Dr. Kingwell

Yeah, definitely. We are in a situation where we have access to some amazing databases. Many of the provinces in Canada have the same or similar databases, so it is like that. We also have the great situation that we have a clinical database in BC too where we've been collecting data on MS patients over a very long period of time. And we can link that data into the administrative databases, so we have the depth of the clinical data that we can link in the breadth of the administrative data, which has really put us in a very strong position to look at these long-term followup studies.

MSDF

Is it pretty smooth to be able to delve into these databases, or do you have any regulatory barriers like, in the US, we have all these HIPAA things. Do you have a problem with de-identifying or anything like that?

Dr. Kingwell

It's certainly not smooth. It can actually take us several years to access this data. It's a long process. It's a lot of paperwork for all of the reasons that…or some of the reasons you just mentioned. The data is actually all handled through…when we're at UBC, it's handled through Population Data BC, which is kind of the center between the Ministry of Health and the databases. And they strip all the identifiers off, so that by the time we receive any data … we, of course, have to go through a lot of privacy concerns and justification before we get any data sets. All the names and the numbers are removed, so that we don't know who anybody is in our database. Even when we're linking our clinical data, of course, everything is completely anonymized by the time we work on anything like that.

MSDF

What kind of conclusions can you draw from what you've found so far?

Dr. Kingwell

One of the main conclusions, I think, is that the incident population has leveled off, apparently, in BC. We started measuring incidence in 1996, and it's possible there were changes in incidence before that, but we can say that in the last 13 years – up to 2008 – that the number of cases has leveled off, which is good news it's not increasing. We also can say that the number of prevalent cases, on the other hand, is increasing a lot, so that the services need to be aware of that that there's going to be a demand on the healthcare system, there already is. And also that our results are very similar to as seen in other parts of Canada and comparable.

The other main conclusion I would draw is that this study really shows how you can utilize these types of databases and reliable algorithms and ways of identifying people with MS in order to monitor the number of people and also changes over time. And also can give us some information about the people with MS and what kinds of drugs they're taking because we're linked into the PharmaNet databases, and we can do that too. So there's lots of questions we can answer about the population in British Columbia.

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MSDF

Thank you for listening to Episode Seventy-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 Carol Cruzan Morton. 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.

[outro music]

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.

For Multiple Sclerosis Discovery, I'm Dan Keller.

 

[intro music]

Host – Dan Keller

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

Today's interview features Dr. Markus Reindl, an Associate Professor of Neuroscience at Innsbruck Medical University in Innsbruck, Austria. We discuss autoantibodies to myelin oligodendrocyte glycoprotein, or MOG, a protein component of myelin. These anti-MOG antibodies are particularly important in pediatric demyelinating diseases.

Interviewer – Dan Keller

First of all, why don't you define MOG for our audience.

Interviewee – Markus Reindl

MOG is myelin oligodendrocyte glycoprotein, and it's a myelin protein which was discovered about 30 years ago. It is of enormous interest to people working in neuroimmunology, because it's one of the main autoantigens used in experimental models for multiple sclerosis. And about 20 to 30 years ago, a lot of people started to work on autoantibodies against MOG in the field of MS because it was suspected to be a key autoantigen. And at that time, there were a lot of papers published with somewhat contradictory results.

About five years, six years ago, the interest of MOG was rediscovered again when people developed more specific assays to detect these antibodies. And surprisingly, it was found that they're not present in classical multiple sclerosis but rather in pediatric demyelinating diseases, such as acute disseminated encephalomyelitis, ADEM, or neuromyelitis spectrum disorders.

MSDF

And what does finding anti-MOG antibodies tell you?

Dr. Reindl

At the moment, it just tells you that if you have these antibodies the risk that you develop MS is minor. So it points to the direction of a different demyelinating disease, which is in most cases monophasic with a good outcome. Or if it's recurrent, it's often recurrent optic neuritis on multiphasic ADEM. Altogether, all this with a good recovery from relapse. Severe disease causes are rare.

MSDF

So in the early stages of MS – something like clinically isolated syndrome – does MOG tell you which direction to go in if you find it?

Dr. Reindl

Usually if you have a clinically isolated syndrome that fulfills the current criteria for multiple sclerosis, looking at the MRI or at the cerebrospinal fluid, it will typically be negative for MOG and autoantibodies, so it's just an exclusion criteria. If you look at the CIS [clinically isolated syndrome], whether it could go to the direction of multiple sclerosis or not, if MOG antibodies are present, the answer would be rather not.

MSDF

Does it fit into neuromyelitis optica, especially seronegative, where there's no anti-aquaporin-4 antibodies?

Dr. Reindl

Yes, it can also be observed in cases with neuromyelitis optica that are aquaporin-4 antibodies negative, particularly in pediatric cases, and often in cases that present with simultaneous optic neuritis and transverse myelitis at onset. So the classical description of neuromyelitis optica by Devic back in the 19th century would rather have been a MOG antibody positive case than an aquaporin-4 antibody positive case. And the pathology of both diseases is entirely different. So in aquaporin-4 mediated neuromyelitis optica, you have an astrocytopathy under high risk of future relapses and disease deterioration. Whereas in the case of MOG antibodies, it's often monophasic, and the recovery is much better.

MSDF

So it sounds like anti-MOG antibodies are not just a marker, but they're actually pathognomonic or pathogenic of the disease.

Dr. Reindl

This is currently under investigation. So what we know from neuropathology there are currently five cases – if I'm correct, or as far as I know – that have been analyzed for neuropathology. These were in most biopsies/autopsies where MOG antibodies were present. And their pathology was in multiple sclerosis type II pathology, which points to the direction of antibody-mediated pathology. So from a neuropathological point of view, looks like MS. If you look at the clinical criteria that are currently valid for multiple sclerosis, it's clearly not MS.

If you look at the pathogenesis, this is currently under investigation. From the in vitro studies, we know that these antibodies can, of course, activate compliment. They also have an affect on oligodendrocyte cell function. In vivo models are currently ongoing, and I expect there to be more results by next year on this.

MSDF

What is the clinical utility at this point? Is it ready for clinical use, or what more needs to be done?

Dr. Reindl

I think particular people working in the pediatric field are using it more and more. Because if you look, for an example, at ADEM, earlier this year we published a study that children with ADEM that are positive for MOG antibodies they have certain features in neuroradiology but also in their clinical presentation and their clinical recovery, which could aid the clinician. In particular, in the European countries, many laboratories are now setting up assays for MOG antibodies and using it in clinical routine. What has to be done now is better development of the assay, a comparison of the assays like it has been done for aquaporin-4 antibodies, like international validation experiments. We're currently setting up such an experiment for next year, together with the people in Oxford and other centers. But, my expectation would be that this antibody would have a similar use like aquaporin-4 antibody has. Also, aquaporin-4 antibodies are more specific for a specific type of disease.

MSDF

You've discussed anti-MOG antibodies in terms of diagnosis. You mentioned prognosis, better course. Can they be useful for following therapy? Do the antibodies actually disappear with immunosuppression, or are they always present?

Dr. Reindl

The point is in the monophasic cases the antibodies disappear anyway. So, I guess in 70% to 80% of all patients – particular the pediatric patients – they have these antibodies at disease onset at high titers, and with time they disappear. They only are persistent if there is a bad recovery or if there's a recurrent disease cause, like recurrent optic neuritis would be an excellent example for this. If you look at therapies, of course, therapies like plasma exchange or corticosteroid used at high doses will lead to a disappearance or a drop of antibody titers. I think we have no really long-term experience, at the moment, because these antibodies were just discovered a few years ago, until long-term studies are ongoing.

MSDF

Is there any work on what triggers these antibodies; whether there's exposure of antigens, what agents may be involved—environmental, genetic, viral?

Dr. Reindl

This is the $100 million question. Of course, we would be happy to know it. It's the similar situation like with aquaporin-4 antibodies. Also there we still don't know it. What is particular interesting is that this is most frequently observed in children at the age under 10 years. These are children that are frequently exposed to infections – the respiratory infections and other infection – therefore it's highly likely that the underlying cause is infectious. But at the moment, as far as I know, there were a couple of studies, at least, but no real systematic study using a lot of patients and with a good epidemiological setup.

MSDF

If there's an infectious agent, is it that it is causing damage to myelin, which is exposing antigens, or there's some crossreactivity with the infecting agent itself?

Dr. Reindl

Both things I think could be possible. The animal models tell us a lot of this. This is work published by Hartmut Wekerle’s group three years ago where they discovered that in transgenic animals – animals that are transgenic for MOG T cells – gut bacteria activate these T cells that go into the brain, and then MOG is released, transported out by dendritic cells to the cervical lymph nodes. And at this stage, the antibodies are induced and built. So it's a rather secondary phenomenon, which is caused by T-cell damage and T-cell destruction. I could imagine that a similar phenomenon could also help in the human situation, particularly if you consider ADEM, which has large lesions, a lot of inflammation going on there. I think it's highly likely that antigen is released, and MOG is one of the most antigenic components of the central nervous system.

MSDF

So what are the big lines of research right now – two or three of them – or the big questions that people are approaching?

Dr. Reindl

At the moment, of course, a better developmental definition of the assay—I guess this is one of the most important—is we're working together – a lot of laboratories, a couple of groups – to improve our assays to come to a common standard and to develop an assay which could be used by different laboratories in the world.

The second is, of course, to better define the clinical and neuropathological diagnosis of the patients presenting with these antibodies. Because at the moment, it's rather diffuse. You have children with ADEM, you have children with optic neuritis, children with myelitis. You have adults with NMO-like symptoms. And to put this together in a better way is, of course, highly challenging, and this is work ongoing at the moment. I think we will have more results of this by the next year.

And of course, the third thing is just to look better at the long-term prognosis of these patients. How these antibodies fits in their long-term prognosis, if they are rather beneficial or not. And this is also work that only can be clarified using larger cohorts of patients and international studies.

MSDF

So is it fairly rare to find anti-MOG antibodies?

Dr. Reindl

In adults, yes. In children, no. So if you look at children presenting with demyelinating syndromes, from our own ongoing study cohort in Germany and Austria—we know it's about a third of all children presenting with demyelinating syndromes—more than a third have these antibodies. If you look at adults, it's much more rare. I guess it's about 5% or less.

MSDF

Well, thank you very much.

Dr. Reindl

You're most welcome.

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MSDF

Thank you for listening to Episode Seventy-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 Carol Cruzan Morton. 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.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[outro music]

Full Transcript:

[intro music]

Host – Dan Keller

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

Today's interview features Donna Osterhout, a cell biologist at Upstate Medical University in Syracuse, New York, USA. Dr. Osterhout talks about a new way of looking at myelin-making cells, which move and change shape in dramatic ways. Current MS drugs take aim at preventing new immune damage. In the future, researchers hope to figure out how to repair myelin and restore function.

But first, let’s look at new content on MS Discovery Forum. Spring brings rain, flowers, and a bouquet of scientific meetings related to multiple sclerosis. See the list at msdiscovery.org under the tab “professional resources.” MSDF sent the only journalist to cover the recent meeting of the American Society of Neurochemistry in Denver, but you can count on a blitz of news from the media pack at the next meeting on the calendar – the American Academy of Neurology in April, happening this year in Vancouver, BC, Canada. The number of research papers about multiple sclerosis has doubled in the last 10 years, and many findings are first reported at meetings before publication.

Moving on, let’s sample a few of the new papers we found in our weekly PubMed search of the world’s largest medical library, the National Library of Medicine. You can link to each week’s list of curated papers at msdiscovery.org.

Related to this week’s podcast, a new paper reviews the latest research about the molecular cues that allow precursor cells to mature and go through the stages of making myelin. These cues come from axons and from other surrounding tissue. Clinical drug development efforts focus on overcoming inhibitory cues, such as with the experimental agent anti-LINGO-1, now completing phase 2 clinical trials for MS and acute optic neuritis by Biogen. The review authors suggest future drugs to repair myelin could boost permissive and promotional cues, which may go wrong in disease. The paper is published by researchers at the Virginia Commonwealth School of Medicine in the journal Experimental Neurology.

Another report updates the Cochrane systematic review on teriflunomide, a daily oral medication for relapsing remitting MS marketed under the brand name Aubagio by Sanofi Genzyme. Cochrane’s systematic reviews are ranked among the highest level of medical evidence, because of the rigorous independent analysis of multiple studies, including randomized controlled trials. The authors write that, as a single drug, the high dose of teriflunomide was as effective as interferon beta 1-a, while the low dose was less effective. They recommended longer follow-up analyses and noted that the available evidence was low-quality, as well as subject to bias, in part because all studies were sponsored by pharmaceutical companies. In general, side effects were mild to moderate and do not usually lead to treatment being stopped, but the higher dose is more prone to cause these side effects. The study is available in the Cochrane Library.

The final editor’s pick this week takes a fresh look at how medical images transform a patient’s view of her own body. The paper describes an artistic collaboration between Devan Stahl, a bioethicist at Michigan State University with multiple sclerosis, and her sister Darian Goldin Stahl, a printmaker. The resulting art – some of it life sized – superimposes Devan’s narrative and MRI images with body photos. Devan wrote in the paper that the art collaboration has made it easier to talk about her MS. The paper is published in the journal Medical Humanities. If you're in town for the big Neurology meeting, you can catch Darian’s artist talk on April 17 at 2 pm at Malaspina Printmakers in Vancouver, Canada.

[transition music]

And now to our interview. We caught up with Donna Osterhout in Denver, Colorado at the March meeting of the American Society for Neurochemistry. She organized a symposium that told a new story about myelin-making cells. In different labs, researchers started looking for clues in the radical shape changes that occur in the cells in their normal process of making myelin. These oligodendrocyte precursor cells sprout “arms” to reach out and touch neighboring axons. Then they push out slabs of fatty membrane and wrap them around and anchor them to the axons. In multiple sclerosis and other demyelinating diseases, the immune system attacks this myelin wrap, and the cells cannot keep up with repair. The unprotected axons may be damaged or destroyed, causing the worsening disability of MS. Learning how the cells make myelin may pave the way toward new therapeutic agents to repair demyelinated axons and restore function. Dr. Osterhout spoke with our executive editor, Carol Cruzan Morton.

Interviewer – Carol Cruzan Morton

So we are here, in Denver, at the annual meeting of the American Society for Neurochemistry, and you've put together a very interesting panel on a new way of looking at myelin. So can you sort of set the scene for us when you're talking about the myelin research that you're working on?

Interviewee – Donna Osterhout

Well, myelin is a specialized membrane that is wrapped around axons; it occurs in the last step of development. And oligodendrocyte progenitor cells are the cells that form myelin. They are going to migrate out through the developing brain and they're going to extend processes that come in contact with axons that need to be myelinated. And when they get the appropriate signals, they are going to start a process by which they synthesize and extend a large membrane, which wraps around this axon many times and compacts and forms myelin.

The way that this happens has been a mystery thus far, but recent research suggests that there has to be a lot of rearrangements of the internal cytoskeleton for this to happen. And so the symposium was organized to talk about how the cytoskeleton might be changing to allow for this membrane wrapping and myelin formation.

MSDF

Can you tell me more about the cytoskeleton?

Dr. Osterhout

The cytoskeleton is comprised of specialized proteins within cells, and every cell has a cytoskeleton; it gives it shape, but it also allows it to migrate, differentiate, and extend processes, so cells wouldn't be able to do much without a cytoskeleton. And in the case of oligodendrocytes, there are a lot of cytoskeletal rearrangements that occur to allow for myelination.

MSDF

Can you tell me more about the emerging view about how myelination may be working based on this new way of looking at it?

Dr. Osterhout

Initially, we know that there are early signals that trigger extensive process outgrowth from these cells. Once the axon sends a signal to the oligodendrocyte progenitor cell, they start to put out many, many processes, synthesize myelin proteins, and make this big membrane that will wrap around the axon. What winds up happening is that in the past everybody thinks that we've needed a driving force so that something pushes this forward, and it had been thought that perhaps the actin cytoskeleton was the driving force behind this.

The newer research indicates that initially you have to have signals that trigger the process outgrowth, but this is followed by an actual disassembly of the actin cytoskeleton. So it's somewhat opposite of what we had thought previously.

MSDF

Can you tell me more about the steps that are involved in the process of myelinating that you and your colleagues have been discovering?

Dr. Osterhout

Well, the initial step is the activation of a cellular kinase called Fyn tyrosine kinase; this is the earliest step in the differentiation of these progenitor cells. Fyn will be activated by any number of signals from the axon including, for example, glutamate that's released. And once Fyn is active, it initiates a rearrangement of cytoskeletal proteins called microtubules in order to facilitate process outgrowth so we can extend processes to form this membrane.

In later stages, then we have Fyn helping to trigger the synthesis of myelin proteins, and then you start to get other proteins active that will disassemble the actin cytoskeleton. There is even some evidence that perhaps myelin basic protein can do this. So Fyn signaling will turn on early and promote the synthesis of myelin basic protein, and then myelin basic protein will proceed down these processes and help to disassemble the actin cytoskeleton so the membrane can wrap around the axon.

MSDF

Can you describe what the cells look like when they're going through this process?

Dr. Osterhout

Well, this is really interesting to study, especially in vitro. You can set up myelinating cultures of oligodendrocyte progenitor cells. They're very simple cells, they're like bipolar, two to three processes, and that's the earliest progenitor that we might look at. But once you trigger differentiation, they start to put out processes in a somewhat predictable manner. They will first extend five processes, and then these five processes start branching And they produce these intricate branches. At some point these mature cells will actually look like a lace doily; they are spectacular with the cell body in the center and all these highly branched processes surrounding it. And then you see a transformation of these processes into this huge membrane sheet, and in the absence of an axon it's just going to cover the tissue culture dish; it's amazing how large this can get. But if you had an axon in the culture, this membrane sheet would just form myelin. They would form a myelin segment wrapping around the axon.

MSDF

That’s so interesting. And then can you say, adding to that picture, the steps that are happening in those process that you and your colleagues have been discovering?

Dr. Osterhout

So when you have the initial process outgrowth, you have Fyn tyrosine kinase active, and that facilitates the initiation and that extensive process outgrowth. But the transition between the process outgrowth and the formation of membrane sheets is going to be the disassembly of the actin cytoskeleton.

MSDF

And that's the big news is that the actin cytoskeleton is breaking down instead of pushing the myelin forward as it's making its multiple wraps around?

Dr. Osterhout

Yes, this seems to be the way that this is happening mechanistically. The formation of that myelin membrane requires the actin disassembly, and two of the speakers that we had in our symposium gave evidence to this, using several different experimental systems. And then ultimately when you're going to anchor this myelin sheath, and you can get some specializations in the axonal membrane, and this is what one of the speakers talked about, anchoring the perinodal loops, kind of the ends of the myelin segment. And so we have a process by which we have extensive process outgrowth triggered by Fyn. Then once you get the process outgrowth, you have actin disassembly and you form these membrane sheets, and then they would wrap around the axon, forming myelin, and then you would stabilize it with special proteins in the axon that stabilize the ends at the perinodal loops.

MSDF

So what does this have to do with diseases like multiple sclerosis?

Dr. Osterhout

That's a very good question. If we understand what goes on in development, then we might be able to predict how we could facilitate this process in a demyelinating disease like multiple sclerosis. We do have oligodendrocyte progenitor cells in our brain and spinal cord. They persist as a population throughout adulthood. And any time you have a lesion or a trauma to the brain, and especially if you get demyelination, then you'll have these cells migrate to the area of demyelination. And if we can encourage them to remyelinate, they would undergo the same steps.

We have shown evidence that the inflammation and other conditions in a demyelinating disease upregulates chondroitin sulfate proteoglycans, and these can actually inhibit the process outgrowth and remyelination by oligodendrocytes, because they ultimately inhibit the activation of Fyn kinase.

So if you're considering a disease process, you want to stimulate these steps. And you want to look for agents that might trigger and make sure that these steps proceed, or neutralize things that would be present in the lesion that would inhibit this.

MSDF

One interesting aspect of your work, and perhaps of science more generally, is that some of these discoveries with relevance to multiple sclerosis come from your work on spinal cord injury. Can you talk about how that works in science?

Dr. Osterhout

Well, spinal cord injury is another type of lesion, it's a specialized lesion; you have damage to axons as well as demyelination due to trauma. But in diseases in general in the brain and the spinal cord, whenever you have an injury process or inflammation or some kind of destruction of tissue, you get an inflammation and immune influx, and you will get a process called reactive gliosis. And this is common to many diseases that you see in the brain. For example, you can see it easily in spinal cord injury, it's been well documented. You can see these proteoglycans' reactive gliosis in multiple sclerosis, you can see it in Alzheimer's disease, Parkinson's disease, and other conditions, because they all have a common element that you've got some kind of inflammation occurring and tissue destruction occurring at a specific place.

MSDF

Getting back to multiple sclerosis and the work on how cells myelinate axons, what are the next big questions that you and your colleagues are asking?

Dr. Osterhout

Well, there still are a lot of questions about exactly how this myelination process is accomplished even during development; we don't fully understand all of the triggers that would activate this process. And, likewise, we don't always understand things that might inhibit this process. So we need to more fully characterize what's going on in development so that we can take a look at it in the remyelinating situations, either in spinal cord injury, or multiple sclerosis, or any other demyelinating condition.

MSDF

Well, that's really interesting. Well, thank you for taking the time to explain the research.

Dr. Osterhout

And thank you for your interest; it's been my pleasure.

[transition music]

MSDF

Thank you for listening to Episode Seventy-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 Carol Cruzan Morton. 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.

[outro music]

 

Transcript:

[intro music]

Host — Dan Keller

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

Today's interview features Nathaniel Lizak, a young Australian investigator from the University of Melbourne who gave the first talk at the recent meeting in New Orleans of the Americas Committee for Treatment and Research in Multiple Sclerosis, or ACTRIMS. Mr. Lizak discusses new findings showing that moderately advanced and advanced multiple sclerosis are more unpredictable than anyone knew, but worsening disability may be slowed by highly effective therapies.

But first, let’s look at new content on Msdiscovery.org.

Our latest data visualization shows statistical snapshots of MS worldwide. Survey data from the MS International Federation show that, as of 2013, the estimated number of people in the world with MS increased to 2.3 million, or about 33 people with MS for every 100,000 people. But MS rates and access to care vary widely from country to country, as you can see from the data visualization.

In a new job posting, the Stanford-affiliated Santa Clara Valley Medical Center Department of Neurology seeks a general neurologist. Subspecialty training in MS, movement disorders, or vascular neurology is preferred. You can post your job at MSDF at no charge to reach researchers and clinicians specializing in MS and related demyelinating disorders.

[transition music]

And now to our interview. Australian medical student, Nathaniel Lizak, and his academic mentors took a second look at how disease progresses in people with moderate and advanced MS and what can be done about it. Researchers are looking for better measures of disability, but the most common one is the Expanded Disability Status Scale or EDSS for short. Lizak and colleagues looked at worsening disease from several starting points, using an international registry known as MSBase that tracks medical record data on nearly 38,000 people with MS. They divided people in three epochs ranging from EDSS 3.0 (where people are moderately disabled but are fully ambulatory) to EDSS 6.0 and higher (where people need assistance to walk short distances). An older study suggested a steady worsening of disease after EDSS 3.0, which Lizak and co-workers questioned. Executive editor, Carol Cruzan Morton, spoke with him about their findings.

Interviewer – Carol Cruzan Morton

We are here at the ACTRIMS meeting in New Orleans, and you opened the conference with a really interesting paper. I wanted you to explain a little bit about what you were asking and why. What area of MS, what questions you are addressing?

Interviewee – Nathaniel Lizak

So we did this work under the MSBase group, which is an MS-based cohorts; it is an international really large study that has data from over 30,000 patients worldwide. We have access to all of their data, and we really thank our contributors throughout the world who have provided this.

We decided – because we have so much power with so many numbers and so much data from patients – to look at the latest stages of multiple sclerosis which, so far, haven't really been that well explored.

There have been three studies in the past which looked at disability and how it progresses in what they have called the moderately advanced stage of multiple sclerosis. So yeah, we looked at disability accumulation in the later stage of multiple sclerosis moderately advanced, which is defined before as between the EDSS steps of 3.0 or 4.0 and 6.0, and we wanted to look at what predicts how the disability accumulates, because a lot of the previous studies didn't really suggest anything really changes disability.

There is this notion amongst doctors that once it hits these thresholds the trajectory is set, and there is nothing you can do to help patients. We didn't believe that. We were hoping there was something you can still do for patients, even once they have already accumulated substantial amounts of disability.

We set this up to look at just how much variability there is in these later stages of disease and what we can do to take it from going really fast to going really slow, to preventing patients from getting even worse.

We used our cohorts, ran lots of statistics, and we found some very interesting results. The first is that this late stage of disease is quite independent from what happens before. How many relapses people have early in the disease, how fast they got to the early disability landmarks, how fast they accumulated disability, if they were on therapy in the past—all of those things don't really seem to impact what happens later on in the disease. That is what we call the amnesic disease phenomenon. That is something that has already been explored in the past. We kind of confirmed that and saw that, that happens at lots of stages in multiple sclerosis.

What is more interesting, though, is that we still found that patients have a lot of variability in what happens to them, even after they have accumulated substantial disability. So in technical terms, after EDSS 3.0, 4.0, and 6.0, there is still a lot of variability in what happens to patients after they have reached these steps, after they have already obtained disability. That suggestion that after the threshold the disease is set doesn't seem to be at all the case. That is all we observed in our patients.

We had over 3,400 patients— we had 3,415 patients exactly. So it is quite I think, generalizable, our results. There is a lot of variation in what will happen at these later stages of disease.

MSDF

You can't predict what happens next. And it is different.

Mr. Lizak

It is different for everyone. It is independent of what happened before, and almost nothing predicts what is going to happen next. The only things that we found which did predict such as how does disability progress in these later stages, the first one was how many relapses they are having now. Not before, not early in the disease, but how many relapses are they now having per year at these later stages?

We found that more relapses later in the disease still contribute to disability. That wasn't something that the other studies had actually shown, and I think that is to do with their methodology more than anything else. I think we are confirming that relapses are still important, inflammation is still important, we still need to treat it, no matter how far along the disability line the patients are. The relapse is still a problem.

A more exciting thing that we found was that the immunomodulatory medications that the disease modifying therapies, the higher efficacies ones, the new medications, the longer patients are on those in the later stages of disease—so again, after those landmarks, after EDSS 3.0, 4.0, and 6.0—he longer patients are on those after they have gone into that disability the lower their likelihood of progressing even further to EDSS 6.0 and 6.5, which is mobility issues needing unilateral assistance or a walking stick, EDSS 6.0 or bilateral walking assistance EDSS 6.5. So those are pretty, obviously, important to patients in being able to move around without needing any aid.

We found that we can prevent patients from getting to these later disability stages with longer time on disease therapies later on in the disease. So the conclusion we got from this is patients should continue being treated later in multiple sclerosis. Of course, it's always a risk/benefit calculation. You always need to take the side effects into consideration and look at the patient that you are seeing. It is not a blanket rule, but there are countries in the world where it's by policy you can't give therapies later on in disease after EDSS 4.0.

New Zealand is one example. In other places in the world, it is just practice to stop giving treatments later in multiple sclerosis, and we are suggesting no there still is a benefit and you should be weighing that up when considering whether or not to continue patients on therapy, whether to start them on stronger therapies. There is evidence that we can still slow down how the disability will accumulate. That was our main message. We were a bit surprised to find out it was not what we were expecting, but we are very happy that we found such results.

MSDF

In your study, what drugs were categories as the high efficacy?

Mr. Lizak

I don't remember exactly every single drug, but we just put into two groups. The low efficacy being primarily the initial very first-line drugs, so interferon, glatiramer acetate, and teriflunomide; everything else categorizes as high-efficacy therapy, so natalizumab, fingolimod, alemtuzumab, dimethyl fumarate, cladribine, mitoxantrone, I might be missing a few. By no means are we saying that one therapy is better than another. We're just looking at the class effect of the really strong medications. We don't yet have the power to say this is the best medication after EDSS 6.0, this is the best medication after EDSS 4.0, or don't go on that one. We're just trying to say that the stronger perhaps second-line therapies often used second-line do have a better effect in this later period of disease, and doctors should be considering that when deciding what treatments their patients should go on, and patients should obviously be made aware of that as well.

MSDF

The idea that things that happen before don't affect the later stages seems on the surface to be at odds with the idea that progressive disease starts early, like treat early.

Mr. Lizak

…to try to treat disease as early as possible. I don't think it is at odds. There's been a lot of work, so far, to say that the earlier you treat your patients the better. We agree with all of that. We are not saying treating later is any better. Probably believe that treating earlier is better, but what we are saying is: a) continue treating, and don't stop treating. I completely agree that all of the patients that we found that after EDSS 3.0, 4.0, and 6.0 improved with more therapy after those landmarks, still probably did better earlier on in their phase of disease with therapy then. But I guess what we saw is the therapy they had earlier in disease won't make an impact now. You need to continue treating these patients for them to have an improvement.

We still absolutely encourage the earlier treatment, the better. That evidence is beyond doubt in multiple sclerosis. We are definitely not challenging that. We completely agree with that. Our evidence just goes and takes it one step further of, the earlier the better, but it is not too late.

MSDF

Now you are doing this study in the context of a clinical practice. How has that changed – or has it changed – how people with MS are treated in the decision making?

Mr. Lizak

The thing is, first of all, I am a medical student, so I don't make any of the decisions. Secondly, where we are based in Melbourne, Australia, there is already a tendency to treat patients later on in disease. Obviously we haven't published the results yet, so we haven't seen how much of an affect it will have worldwide. Perhaps now we will begin to start changing things. But in Australia where nothing was studied, no one was surprised to find that this was the case. All the doctors there already treat their patients later on in the disease. So it just confirmed that what they are doing is correct. No one has yet drastically changed how they are treating patients. We hope though that, say countries like New Zealand whereby policy after a certain EDSS score, after EDSS 4.0, after moderate disability has been accumulated, you can't put patients on disease-modifying therapy anymore—we hope that is where we will have the biggest impact.

MDSF

When you gave your talk, you talked about the earlier study. There wasn’t an appreciation for the variability. How did you come to ask that question in the first place?

Mr. Lizak

I have to give credit to my supervisor, as well as the whole MS based team that was behind this study, and obviously they conceptualized it a lot more than I: Dr. Thomas Kalincik and Helmut Butzkueven, in particular. But a lot of doctors, particularly our team, are not happy with that graph. Which it looks like everyone after EDSS 3.0 has the same trajectory. We looked at this, and we thought we wanted to do a study to prove this wrong. We didn't know exactly what we were going to find. We actually proved that what they first suggested of disease being independent to be quite correct. But they just missed the variance in the second half. It is independent, but it is still really variable.

We looked at the graphs carefully, and we looked at the study carefully, and we made the note of they only have a mean value on that top half, they don't show how much variability there may or may not be in disease. We got confused. We said it is unlikely that patients have no variability at all after EDSS 3.0, and we decided not only are we going to look at what predicts the later disease, but we need to know just how variable is this disease this late, and we found that it is extremely variable. After EDSS 6.0, patients might go straight through to worse disability, and many will improve, and many will stay stable for many years. We were just unhappy with the message that the graph gave. Then we tried to scrutinize exactly where can we change this message, where can we improve this.

MDSF

That’s great. What questions are your colleagues asking you here about the study?

Mr. Lizak

I have had a lot of questions about this study, some more helpful than others. A lot of people have asked how will this change management? And I think we have just spoken a little bit about that. I am asked, as well, how do you tell patients that we can no longer predict their disease? We used to think that we could and now we just outright can't predict their disease and that is something that is going to be difficult to tell the patients. I think you need to frame it differently. It is not we can't predict how your disease is going to go, it is, we have hope for making it better. You might have been doing not so well up until now, but we still have hope to continue fighting. We haven't given up yet. And I think that is what we need to be framing it as. That is one of the questions I have gotten the most.

A lot of people have asked about why we chose certain therapies, and there is very little evidence about which therapy is high and which therapy is low. We just used the available studies as well as the clinical experience and just compared how much they reduced relapse rates and so on. It was partly based on intuition and observation. It could be the case that some therapies should have been classified differently to what we did, but it is very hard to tell at this stage.

Even then, even looking at the list, you should be mindful that a therapy that we classified as high efficacy might have actually been bringing that group down. And maybe should have been a low efficacy therapy, and maybe a low efficacy therapy was the only one working in that group, and it should have been in the high efficacy group. So obviously, be very careful when you look at that.

At that strata, it is not meant to be telling anyone I should be on that drug or I shouldn't be on that drug. It is just meant to be saying that strong medications are better in this stage, but the decision of the medication should be a decision made entirely by the patient and their doctor, and it should only be used to influence and it shouldn't be taken any more than that.

MDSF

Is rituximab in your …. I was going to say before a B cell therapy.

Mr. Lizak

I don't think we have many patients on rituximab, but we would have had quite a few. Yes, because it was used quite extensively.

MDSF

Thanks. Is there anything else that I haven't asked or that you wanted to add?

Mr. Lizak

Rituximab wasn't the high efficacy group. I should mention that. Yes. Thank you for the fantastic opportunity to showcase the work we have been doing. I obviously have to give credit to everyone at MSBase who conceptualized and gave patients the study. We couldn't have done it without the help of our collaborators worldwide.

[transition music]

MSDF

Thank you for listening to Episode Seventy-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 Carol Cruzan Morton. The data visualization was developed by Jean Mercier of Khawai Data Visualization at Khawai.com. 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.

[outro music]

 

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.

For Multiple Sclerosis Discovery, I'm Dan Keller.

 

 

 

Transcript to come soon

[intro music]

Host – Dan Keller

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

In today's interview, we'll talk with Dr. Brian Weinshenker of the Mayo Clinic about new diagnostic criteria for neuromyelitis optica spectrum disorder and how it differs from MS. The new criteria build upon and broaden the definition of NMO that was based, in part, on the presence of antibodies to aquaporin-4.

But to begin, let’s sample a few of the new studies we found in our weekly PubMed search of the world’s largest medical library, the National Library of Medicine. You can link to each week’s list of curated papers at msdiscovery.org.

On topic with our interview, an international team led by researchers in Tianjin, China, found a unique group of people with neuromyelitis optica spectrum disorder, or NMOSD, who carried autoantibodies to both aquaporin-4 and myelin oligodendrocyte glycoprotein or MOG, a minor component of myelin. Among the 125 patients, 10 were double positive for both sets of antibodies, and 14 were positive only for MOG. The double-positive patients had a worse disease course, most having MS-like brain lesions and more disability. Those with only MOG antibodies had a milder disease and less disability. If verified in other studies, the findings may help predict the clinical course of NMOSD or even define a new phenotype somewhere between the two very different diseases of NMOSD and MS. The authors say their paper also raises a new challenge of how to diagnose and treat such patients. Three double-negative patients did not respond to rituximab, a highly effective anti-B cell therapy used off label for MS and NMO. The study is published in the journal Science China Life Sciences.

For people with MS and other demyelinating conditions, bladder issues can play an oversized role in the quality of life. A pair of review articles addresses the “neurogenic bladder.” One from Duke University researchers in North Carolina, USA, recommend an evaluation known as urodynamics, calling it the gold standard in helping to break down the complex problem into basic and treatable factors. In the other paper, researchers from Western University in Ontario, Canada, review the 16 different ways to measure patient reported outcomes for neurogenic bladder, and how to choose the best one to track patients’ quality of life. Both reviews are published in the journal Translational Andrology and Urology.

In the news section, MS Discovery Forum correspondent Stephani Sutherland wrote about the recent negative results of fingolimod in a large Phase 3 clinical trial of people with primary progressive MS. Even in failure, studies can be informative and can help researchers design better investigations to test potential therapeutics for progressive disease.

Now, let’s move on to our drug development database. The drugs with important additions and changes are daclizumab, fingolimod, and ocrelizumab. One update reflects findings presented at last month’s ECTRIMS conference in New Orleans suggesting that in primary progressive MS, the experimental drug ocrelizumab reduces disease activity in subgroups of individuals with and without gadolinium-enhancing images at baseline.

[transition music]

And now to our interview. It’s been 11 years since neuromyelitis optica, or NMO, was redefined as a separate disease from MS. Thanks to the discovery of the first biomarker for NMO, an antibody against aquaporin-4, diagnostic criteria for neuromyelitis optica, or NMO, were revised. In today's discussion, Dr. Brian Weinshenker of the Mayo Clinic in Rochester, Minnesota, USA, lays out further revisions to the criteria and the reasons for them. He uses a couple of terms that may warrant definition. One is IgG, which is immunoglobulin G, a particular class of antibody. Other terms are seropositive, meaning, in this case, the presence of antibodies to aquaporin-4, and conversely, seronegative, the absence of such antibodies. Finally, ADEM, A-D-E-M, is acute disseminated encephalomyelitis, a sudden, widespread attack of inflammation in the brain and spinal cord, usually seen in children. I spoke with Dr. Weinshenker at the ECTRIMS meeting last fall in Barcelona about the new consensus diagnostic criteria for NMO.

Interviewer – Dan Keller

Is there something that was lacking before?

Interviewee – Brian Weinshenker

Well, the first diagnostic criteria for neuromyelitis optica were proposed by our group at Mayo Clinic in 1999. And in 2006, with the advent of the first diagnostic biomarker for neuromyelitis optica, an antibody which we now know is directed against aquaporin-4 – I’ll call it aquaporin-4 IgG – the criteria were revised. But there was a need to revise them. We became increasingly confident in this diagnostic biomarker, and it was possible to make an earlier diagnosis, often after the very first symptom. So that was one key driving factor.

And furthermore, with the advent of this biomarker, we’ve appreciated that the spectrum of this disease is far broader than we had previously recognized. And there are a number of clinical syndromes that were previously not recognized as being part of the neuromyelitis optica spectrum that we now know are, and those needed to be integrated. Another key factor was the fact that a number patients that we recognize have this same condition now did not meet the old criteria. For example, you had to have both optic neuritis and myelitis to make this diagnosis, and we recognize some patients with this condition have just recurrent myelitis or just recurrent optic neuritis; they wouldn’t have satisfied the criteria. So those were the key reasons that drove developing new criteria.

MSDF

What are some of the new criteria?

Dr. Weinshenker

The first important point is that we’ve eliminated distinction between neuromyelitis optica – that is, having optic neuritis and myelitis – and having some of these more limited forms or unusual forms of the disease with brain lesions. And we’ve used the term neuromyelitis optica spectrum disorder to refer to all of them.

Second aspect of the diagnostic criteria is that we’ve stratified them based on whether or not you have this biomarker, the aquaporin-4 IgG. And we’ve separately defined patients with that biomarker and those without, the largest group being those with the biomarker. So in the patients with this biomarker, we really require only one clinical syndrome. The clinical criteria are very, very liberal, and we don’t even require, say, for myelitis, as we had before, we used to require having a long spinal cord lesion. We now recognize that about 10 to 20% of patients do not have those kind of long spinal cord lesions when they have a myelitis, so we no longer require it if you have that biomarker.

But we’ve left open a category that we call seronegative neuromyelitis optica spectrum disorder, because some patients who meet all of the various clinical criteria’s, even the strictest clinical criteria, seem to be seronegative for this biomarker. We recognize that’s a heterogeneous group of patients; some of them ultimately will become seropositive. In some of those patients, we’re recognizing other antibodies that seem to be associated with a similar clinical syndrome, so I think, ultimately, we may create new silos based on those biomarkers, but when these criteria were developed, it was felt to be premature to include other antibodies as diagnostic biomarkers. So we’ve grouped them into this group of seronegative NMO spectrum disorder.

But we’re much more strict in that category. We do require two clinical syndromes – two different clinical syndromes – and in some situations we do require additional MRI criteria in order to meet those criteria.

MSDF

Okay, because it was sounding like you were being so liberal about it people could lack this symptom and that symptom and antibody, but, in this case, if they’re lacking antibody, they need other criteria to qualify.

Dr. Weinshenker

That’s correct; both clinical and radiologic criteria. And we also have exclusionary – well, I shouldn’t say exclusionary. There are no exclusionary criteria. We refer to them as red flags. If you have certain characteristics that would make it more likely that you have MS, which is the major competing diagnosis, or if you have certain comorbidities like, say, cancer or sarcoidosis – we know sarcoidosis can sometimes mimic neuromyelitis optica – we add that as a note of caution, but strictly, no criteria is considered exclusionary for a diagnosis of neuromyelitis optica spectrum disorder.

MSDF

Would other systemic autoimmune states also fall into the category of red flags: we’re going to have to decide whether it really is NMO or not?

Dr. Weinshenker

Actually, that used to be excluded by some people that if patients had systemic lupus or Sjögren's disease they were excluded, but we recognize that patients with neuromyelitis optica spectrum disorder have an excess of those other autoimmune diseases. We very frequently detect comorbid disease, so we actually say that, say, a diagnosis of lupus or Sjögren's actually increases the chances that his patient has neuromyelitis optica spectrum disorder if they present, say, with optic neuritis or myelitis. The old literature was replete with patients who were described as having lupus myelitis. Actually the majority of those patients actually have comorbid neuromyelitis optica spectrum disorder. So it’s no longer an exclusionary criterion.

MSDF

There used to be a requirement for bilateral optic nerve involvement? Is that right? Has that gone by the wayside?

Dr. Weinshenker

Yes, this is before there were actually formal criteria, but yes, that was considered to be, say, a red flag that you might be dealing with neuromyelitis optica compared to standard MS. We recognize that that applies to a relatively small percentage of patients, so it doesn’t really appear in these current diagnostic criteria, but certainly it would not exclude it. And I would say that it does add to the suspicion that someone has neuromyelitis optica spectrum disorder compared to MS.

MSDF

What about pediatric neuromyelitis optica spectrum disorder?

Dr. Weinshenker

We did have several people, who were pediatrics experts, on our international panel and, in general, it was felt that the same criteria that we’ve applied to adults can be applied to children. We do recognize that certain brain syndromes are relatively more common in children, and there is one caveat, that is, in pediatric multiple sclerosis, sometimes patients will have long spinal cord lesions, and that’s one of the criteria that adds to the suspicion that somebody has NMO spectrum disorder as to MS. It may be somewhat less reliable in children.

MSDF

Is there any confounding or concern about ADEM in children?

Dr. Weinshenker

Well, neuromyelitis optica spectrum disorder can be associated with brain lesions that can be interpreted as ADEM. They can be large, tumefactive, extensive. Brain biopsy, which is not part of the criteria that we use for neuromyelitis optica spectrum disorder, can sometimes differentiate ADEM – standard ADEM – from the ADEM-like lesions that occur in neuromyelitis optica spectrum disorder, so yes, it can be a diagnostic problem. But generally speaking, if one relies on the other criteria – the presence of optic neuritis and myelitis, which can occur in both ADEM and neuromyelitis optica spectrum disorder – usually one can come to a clinical diagnosis. But there are some situations that can be confusing and occasionally additional tools, even brain biopsy, can be necessary to make a definitive diagnosis.

MSDF

If serologic testing is not available, do you still require the two other criteria to make the diagnosis?

Dr. Weinshenker

We propose that, for now, if serologic testing is not available – and there aren’t many places in the world where it’s strictly unavailable; it is offered worldwide – that you rely on the criteria for the seronegative and satisfy those criteria of seronegative NMO spectrum disorder.

MSDF

Are the criteria fairly straightforward that any neurologist up-to-speed can interpret them and use them clinically?

Dr. Weinshenker

Yes. We have designed these so that they can be used by neurologists in standard practice. Obviously, they don’t cover every single possibility, and there are complex patients where consultation will be necessary, but these are designed to be as good any diagnostic criteria can be. I think one has to realize that diagnostic criteria are for typical patients with conditions, and there are rare situations in difficult-to-interpret situations where one does need this kind of consultation.

MSDF

What about other historical terminology, and what kind of recommendations have you made vis-à-vis that?

Dr. Weinshenker

This has been a confusing element of the literature. For example, one term used in Asia, where it was recognized that you can have a relapsing condition that primarily targets the optic nerves and spinal cord was often referred to as Asian or Japanese opticospinal MS. And historically, this has been a very important contribution. I think our colleagues in Asia were the first to recognize that this relapsing condition was distinct from MS and may be something different, but the terminology was confusing. It was called opticospinal MS. Was this MS or something distinct from MS? And was it the same as neuromyelitis optica?

And the panel felt that this term is no longer useful in clinical practice, and it doesn’t distinguish from multiple sclerosis. So it was felt all of those patients could be probably put into either the NMO spectrum disorder category or multiple sclerosis category, proposed that, for clinical practice, that terminology be eliminated.

MSDF

This is a good way to make the diagnoses, but it leads into the question of then what do you do? And next week’s podcast will focus on new clinical approaches to looking at NMO.

[transition music]

Thank you for listening to Episode Seventy 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 Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. 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.

For Multiple Sclerosis Discovery, I’m Dan Keller.

[outro music]

Transcript will be available soon.

Transcript to come soon

Full Transcript

[intro music]

Host – Dan Keller

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

We’ll hear from Neda Razaz, a doctoral candidate at the University of British Columbia in Vancouver, Canada, on her research looking at what it means for child development when a parent has MS. The findings may help parents and health care professionals define strategies and services for children when needed.

 First, let’s check out a few of the 70 new research papers we found in the last week. You cn see each week’s list of curated papers at msdiscovery.org.

There’s a large and confusing cast of players in demyelinating diseases, such as MS and neuromyelitis optica spectrum disorders. But if the central nervous system was a stage set in a spaghetti Western movie, at least everyone knows the bad guys wearing black hats would be the T cells, right? Hold your horses, say the German and U.S. authors of a review paper in the journal Trends in Immunology. New findings in the last year reframe the story. Some T cells wear white hats. In fact, the central nervous system may need T cells to limit opportunistic infection, inflammation, and damage. Some MS drugs may work by redirecting T cell behavior. Side effects of other MS drugs may come from blanket suppression of all T cells.

Now is the time to cue the theme from the movie Jaws. In the history of life on Earth, the kind of myelin that researchers are trying to protect and restore in people with MS and related disorders first showed up in a family of shark-like fish and skates and rays. The first true myelin basic protein seems to have originated in this family of cartilaginous fish, called chondrichthyans, or their ancestors. This information comes from an article in a special issue on myelin evolution in the journal Brain Research.

A third paper that caught our attention looks at modern myelin. Almost every cell in the body has little energy packs called mitochondria. That’s true with brain cells, including the oligodendrocytes that make the myelin membrane that wraps around axons. Researchers from Norway say they have shown, for the first time, mitochondria moving into the myelin wrap. They also report that oligodendrocyte mitochondria are smaller, slower, and move less often than those in astrocytes and neurons.

Now, to our drug development database. The drugs with important updates this week are fingolimod, glatiramer acetate, interferon beta-1a, mitoxantrone, and natalizumab. One update summarizes a press release indicating that a generic version of fingolimod has been launched in Russia.

[transition music]

And now to our interview. The University of British Columbia in Vancouver, Canada, has a strong program in MS. We spoke with several of their researchers at the ECTRIMS meeting in Barcelona last fall. Today Neda Razaz, a PhD candidate, fills us in on her work on the impact of living with a parent with MS on child development or wellbeing

Interviewee – Neda Razaz

I study a group of parents with MS and their children, and we actually use health administrative databases to capture our cohort of interest.

Interviewer – Dan Keller

And what were the outcomes of interest, and how did you assess them?

Razaz

So, for one particular study that was actually published recently, we were interested in child developmental outcome at kindergarten. So I used the Early Child development instrument, which is a routinely collected database by kindergarten teachers in their classroom. And the specific instrument measured children’s wellbeing from social, emotional, and physical wellbeing. And that was our outcome of interest for that particular study.

MSDF

What did you find?

Razaz

I actually found that children who have a parent with MS were doing as well as children without a parental MS, so having a parent with MS was not associated with adverse developmental outcome.

MDSF

Was any aspect of parental mental health associated with children’s outcomes?

Razaz

Actually, yes. In the study, when we did a sensitivity analysis, we found that, in parents who had mental health condition, children were at higher risk of developing some adverse developmental outcomes, specifically in their social and emotional domains of their development.

MSDF

Could you tell if these parental mental health aspects had anything to do with the MS

Razaz

We didn’t specifically look at that, but it is very well-known in the literature that mental health is highly associated with MS. So we kind of feel that it’s not the MS particular; it’s the comorbidities that come with MS that might have an impact on the child.

MSDF

Did it matter whether it was the father or the mother with the issues?

Razaz

We did look at gender specifics, and in one study we did find that having a father with MS who had a coexisting mental health morbidity was also having an impact on child developmental outcome. Specifically for the fathers, it was their emotional wellbeing. But, however, for most of our studies we probably didn’t have enough fathers to be able to see a meaningful difference.

MSDF

Could you get a handle on alcohol use?

Razaz

No, I – we didn’t specifically at that, no.

MSDF

In the case of maternal MS, did it matter whether the disease was present during pregnancy, or if it arose sometime later in childhood development?

Razaz

We didn’t specifically examine the timing of the maternal MS onset, so I can’t comment on that specifically, but our inclusion criteria was that MS had to occur some time before the child reached five years of age. And 60% of our MS cohort had their first onset of MS after their pregnancy

MSDF

Does that give you any clue into the child’s duration of exposure to these issues?

Razaz

We did look at that, and in one study we found that there was a significant association between the duration of the child’s exposure to parental MS and adverse developmental outcome. And I actually feel that’s a very important question, and I’m exploring this further in my future studies as well.

MSDF

Can you put this into context? How does it compare to parental issues in other diseases?

Razaz

Some of our findings are broadly consistent with other chronic illnesses and is actually a specific meta-analysis looking at children who have parents with medical illnesses found that, overall, these children higher rates of internalizing behavior such as anxiety, depression, compared to children who don’t have parents with MS. However, most of these studies, their study population were adolescents, and it’s kind of different from ours kindergarten-aged children. So that might explain some of the differences in the findings that we found. So maybe being that young, at age five, is too early to have any impacts. And also maybe the parents with MS, their disease is not as advanced

MSDF

Are you or someone else going to follow these children as they age?

 

Razaz

I am interested in actually – you know, my future studies I would like to do a longitudinal study of following these children until older ages; so at least until the time they are 18, and see whether they have a different rates of mental health disorder compared to children who don’t have a parent with MS. I’m interested in, like, specifically living with a parent with a chronic illness.

MSDF

What are the implications of your findings, and can you make any recommendations?

Razaz

While other studies are needed to confirm our findings, we believe that health professional need to be aware of the effect of mental health morbidity that is commonly associated with MS and its impact on their families. And we believe that mental illness such as anxiety and depression among MS patients should suggest the need for appropriate support for their children, because these children seem to be at higher risk of having some adverse developmental outcomes.

MSDF

What have we missed or is important to add?

Razaz

So I just want to say that these studies represent the first important steps in making a difference in MS. We are describing and exploring association, however; we and others in the field need to know if intervention at any way can make a real difference in the lives of parents and their kids.

MSDF

Whom would the intervention involve?

Razaz

The intervention should be family-centered intervention, having the MS patient and also the other parent and other children in the household. So it shouldn’t be individualistic, and it should be the whole family as well.

MSDF

Very good! I appreciate it. Thanks.

Razaz

Thank you very much.

MSDF

Two months after this interview, in late December, the findings were published in the journal Multiple Sclerosis. The paper is free and open to non-subscribers, and you can find a link to it on the podcast page on msdiscovery.org. There you can also find links to be papers and drug development database.

[transition music]

MSDF

Thank you for listening to Episode Sixty-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 Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. 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.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[outro music]

Transcript will be available soon.

Transcript available soon.

[intro music]

Host – Dan Keller

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

We’ve just passed the winter solstice. What better time than the shortest daylight hours of the year to check in with research at the University of British Columbia on sunlight and MS? Today we talk with Dr. Helen Tremlett who is exploring sun exposure over a person’s life course and how that syncs with their MS risk and disease course.

In the weekly papers section on the MS Discovery Forum, this week’s list includes nearly 150 newly published research reports that could lead to better understanding and treatment of MS and related disorders.

We selected four papers as editor’s picks. In one paper, researchers think they may have the first experimental evidence that MS may start with damage or loss of myelin-making cells in the brain and spinal cord. In this new mouse model of progressive MS, experimentally damaged brain cells make it hard for the mice to walk. The mice recover when their brain cells repair on their own. Six months later, the MS-like disease returns. In the study, the team showed that nanoparticles targeting the autoimmune reaction prevent the second phase of the disease. The study shows support for an “inside-out” model of MS. That’s different from the “outside-in” model, in which some aspect about the immune system goes wrong and then initiates the attack on myelin-making cells. The paper is published in Nature Neuroscience by collaborating researchers from Northwestern University and the University of Chicago.

To grow and be healthy, all human cells need a signaling molecule named mTOR, named for the mammalian target of rapamycin. That’s true for myelin-making cells, or oligodendrocytes, as listeners may remember from an earlier podcast interview with Dr. Wendy Macklin. The ability to make myelin seems to depend on a key part known as mTOR complex 1, also called its raptor subunit. In a very basic advance, scientists have determined the atomic architecture of the raptor, or mTORC1, piece. The details are reported in the journal Science and provide a structural basis for studying mTORC1 function.

In another editor’s pick, a review of cases of pediatric neuromyelitis optica, or NMO, showed that new international diagnostic guidelines applied well to children. Unfortunately, they also found that children with NMO have delayed treatment and worse short-term outcomes compared to those with MS. The authors urged immediate adoption of the guidelines to select the best treatment and improve outcomes.

In the fourth editor’s pick, researchers found a potential new target to protect axons in a mouse model of neurodegeneration in multiple sclerosis. The target is a pore in the mitochondria, the cellular battery that provides energy. They designed a molecule to block the pore and showed it helped protect neurons and improved the mice’s mobility, all with minimal immunosuppression. The paper by mostly UK researchers is published in the Journal of Biological Chemistry.

Now, let’s take a look at the latest Drug Development Pipeline updates. The drugs with important additions and changes are dimethyl fumarate, fingolimod, glatiramer acetate, natalizumab, and rituximab. One update reflects findings from post-hoc analysis of clinical trial data showing that the positive effects of fingolimod are apparent quite soon –within months – after initiation of treatment.

[transition music]

And now to our interview. I spoke with Professor Helen Tremlett, Canada research chair in neuroepidemiology and multiple sclerosis at the University of British Columbia when we were at the ECTRIMS conference in Barcelona in October. She has been studying sun exposure over the course of the lifetime and its relation to MS risk. While MS may affect an individual's likelihood to go out in the sun, studies may also need to consider the influence of sun exposure before the disease develops.

Interviewer – Dan Keller

What are you doing in this area?

Interviewee – Helen Tremlett

So I was presenting at ECTRIMS yesterday on a really interesting study based out of the Nurses' Health Study, and this was a collaboration from my group in Vancouver and Harvard School of Public Health; and that's Alberto Ascherio's group and Sandy Munger. So we were looking at sun exposure over the life course and associations with multiple sclerosis. So here we were looking at both aspects of the spectrum, if you can imagine; we were looking at sun exposure and future risk of multiple sclerosis, but also once an individual has developed multiple sclerosis, we were looking at the impact that potentially has on an individual in terms of their propensity to go outdoors in the daylight hours, outdoors in the sun.

MSDF

Right. So it may be the cart is before the horse in that sense; not that sun exposure is causing it, but their disability is causing less sun exposure?

Dr. Tremlett

We were looking at both sides of the equation. And I think it is important, particularly in a disease such as MS where onset of MS is a little bit fuzzy, I think, to look at sun exposure of the life course is important, and certainly our findings are indicating that. Because you want to know sunlight exposure in MS risk, but you also want to know, once someone's developed multiple sclerosis, how that influences their behavior outdoors and what implications that has if you're then trying to design the study to look at what causes MS.

You need to be really careful who you recruit, because if that person has already changed their behavior, then that may influence your findings, and you're not then actually looking at what causes MS at all, you're just looking at a consequence of the disease. So I guess that's the first part of why we wanted to do that.

And the second part is if having MS, if having a chronic condition, does influence your propensity or ability or desire to go outside, what consequence could that have for your health in terms of maybe your serum vitamin D levels or your melatonin levels, and that may have a consequence in terms of long-term health.

MSDF

You segmented people by where they were and at what ages.

Dr. Tremlett

It was pretty interesting. So, first of all, over ages 5 to 15, we found there that there was a 48% lower risk of MS for women living in high, relative to low, ambient UVB areas during their sort of childhood and early adolescent years. So that was pretty interesting. But we found, kind of to our surprise because it goes against other studies that are out there, we found that time spent outdoors in summer or winter wasn't significantly associated with MS risk in that age group, 5 to 15 years. But what we didn't realize is that it wasn't until we combined that outdoor behavior with the UVB, then we could see that there was an association. So we found that less time spent outdoors in summer in low ambient UVB areas—that was associated with a two-fold increased risk of multiple sclerosis.

That was an important step for us; I mean, it might, you know, sound obvious to combine those two, but it was an important step because other studies in smaller geographical areas such as Tasmania, or there's a study out of Norway in a small region of Norway, they can find an association between time spent outdoors in summer/winter and MS risk. But I think we couldn't find it in the US, because the US is at such a diversity of latitudes – the study spanned over 14 US states – so it wasn't until we looked at that outdoor behavior in context of ambient UVB that we could find the association.

And then, I suppose, our next step was to look at outdoor behavior over the life course. And this was really interesting, that we found some avoidance behavior was apparent in later life in multiple sclerosis. And maybe that comes as no surprise to people, but I think our numbers are interesting to put a concrete figure on it. So, for instance, by age 50, our MS cases were 60% less likely to report high relative to low outdoor exposure compared to controls, and that was in winter and in summer.

So the bottom line is people with MS, once they have MS, are not going outside as much, so they're not getting that UVB exposure, so potentially they're not making that vitamin D and serum vitamin D. And then the winter exposure's important as well, because potentially they're not getting the same melatonin production and inhibition, and that may have a really important role in terms of immunology, the circadian rhythm and your sleep cycle, which, again, all knocks back into overall health and immunology of MS. And there have been some presentations actually at this conference looking into melatonin and its association with relapses in MS, and that's pretty interesting.

MSDF

There's even some emerging thought that sleep is essential for good brain function in terms of taking out the garbage – glymphatics and things like that. So melatonin disturbances may actually have some further consequences in an inflammatory brain disease.

Dr. Tremlett

And there's some interesting studies, not that we did but others have done, looking at shift work and risk of MS. And shift work may be associated with increased risk of MS. Maybe melatonin ties into that as well.

MSDF

Is there also potentially an effect, besides on vitamin D and melatonin, that sun exposure itself has an effect on the immune system, maybe suppressing it?

Dr. Tremlett

Yeah, modulating it in some way. No, absolutely. We don't really know the mechanism. I mean, the obvious one would be sun on human skin at the right time of year on the right skin color can result in really high levels of serum vitamin D being produced. Sunlight exposure the minute it actually hits the skin surface can have a direct immunomodulatory effect. And then, obvious, sun hitting the eye. Melatonin is one of the pathways in there that may then impact the immune system.

MSDF

Is it possible to make any conclusions or even recommendations at this point?

Dr. Tremlett

No. It's an observational study, and we do actually need to do more analysis on this group of individuals. The main recommendations we could make from this study is informing how to design future studies, and also two things you could take from this in terms of recommendations.

First of all, we saw sun avoidance behavior in individuals once they've developed multiple sclerosis. That's really important because it really means that if you want to look at what is causing MS, do not take serum vitamin D levels or look at skin cancer risk, for instance, in individuals who already have MS, because they've already changed in compare to controls, adding further somehow differences are related to what causes MS, because these individuals have already changed their behavior because they've got a chronic disease. So that's the first statement, which might be a no-brainer for some people, but it's amazing how many studies are still published like that in the MS literature at the moment.

And I suppose the second piece is trying to understand if we are going to do an interventional study, what time period in an individual's life or within a population do you need to target in order to change the course and prevent the disease from occurring? And we're trying to understand that more, looking beyond the window age 5 to 15, look more into adulthood to see if ambient UVB is associated with MS risk later in life and into adulthood. And others have shown that there does seem to be an association even into adulthood, which is exciting because if you do want to do an intervention study, then you haven't necessarily missed the boat because you've not intervened during childhood. But, I mean, the real question is how do you intervene and what with? And that's another topic in itself.

MSDF

We'll leave that for another day. Thank you.

Dr. Tremlett

Thank you very much.

[transition music]

Next week, we'll continue our discussion with Professor Tremlett when she'll talk about her preliminary studies on pediatric MS patients and their gut microbiomes.

Until then, thank you for listening to Episode Sixty-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 Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. 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.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[outro music]

[intro music]

Host – Dan Keller

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

We’ve just passed the winter solstice. What better time than the shortest daylight hours of the year to check in with research at the University of British Columbia on sunlight and MS? Today we talk with Dr. Helen Tremlett who is exploring sun exposure over a person’s life course and how that syncs with their MS risk and disease course.

In the weekly papers section on the MS Discovery Forum, this week’s list includes nearly 150 newly published research reports that could lead to better understanding and treatment of MS and related disorders.

We selected four papers as editor’s picks. In one paper, researchers think they may have the first experimental evidence that MS may start with damage or loss of myelin-making cells in the brain and spinal cord. In this new mouse model of progressive MS, experimentally damaged brain cells make it hard for the mice to walk. The mice recover when their brain cells repair on their own. Six months later, the MS-like disease returns. In the study, the team showed that nanoparticles targeting the autoimmune reaction prevent the second phase of the disease. The study shows support for an “inside-out” model of MS. That’s different from the “outside-in” model, in which some aspect about the immune system goes wrong and then initiates the attack on myelin-making cells. The paper is published in Nature Neuroscience by collaborating researchers from Northwestern University and the University of Chicago.

To grow and be healthy, all human cells need a signaling molecule named mTOR, named for the mammalian target of rapamycin. That’s true for myelin-making cells, or oligodendrocytes, as listeners may remember from an earlier podcast interview with Dr. Wendy Macklin. The ability to make myelin seems to depend on a key part known as mTOR complex 1, also called its raptor subunit. In a very basic advance, scientists have determined the atomic architecture of the raptor, or mTORC1, piece. The details are reported in the journal Science and provide a structural basis for studying mTORC1 function.

In another editor’s pick, a review of cases of pediatric neuromyelitis optica, or NMO, showed that new international diagnostic guidelines applied well to children. Unfortunately, they also found that children with NMO have delayed treatment and worse short-term outcomes compared to those with MS. The authors urged immediate adoption of the guidelines to select the best treatment and improve outcomes.

In the fourth editor’s pick, researchers found a potential new target to protect axons in a mouse model of neurodegeneration in multiple sclerosis. The target is a pore in the mitochondria, the cellular battery that provides energy. They designed a molecule to block the pore and showed it helped protect neurons and improved the mice’s mobility, all with minimal immunosuppression. The paper by mostly UK researchers is published in the Journal of Biological Chemistry.

Now, let’s take a look at the latest Drug Development Pipeline updates. The drugs with important additions and changes are dimethyl fumarate, fingolimod, glatiramer acetate, natalizumab, and rituximab. One update reflects findings from post-hoc analysis of clinical trial data showing that the positive effects of fingolimod are apparent quite soon –within months – after initiation of treatment.

[transition music]

And now to our interview. I spoke with Professor Helen Tremlett, Canada research chair in neuroepidemiology and multiple sclerosis at the University of British Columbia when we were at the ECTRIMS conference in Barcelona in October. She has been studying sun exposure over the course of the lifetime and its relation to MS risk. While MS may affect an individual's likelihood to go out in the sun, studies may also need to consider the influence of sun exposure before the disease develops.

Interviewer – Dan Keller

What are you doing in this area?

Interviewee – Helen Tremlett

So I was presenting at ECTRIMS yesterday on a really interesting study based out of the Nurses' Health Study, and this was a collaboration from my group in Vancouver and Harvard School of Public Health; and that's Alberto Ascherio's group and Sandy Munger. So we were looking at sun exposure over the life course and associations with multiple sclerosis. So here we were looking at both aspects of the spectrum, if you can imagine; we were looking at sun exposure and future risk of multiple sclerosis, but also once an individual has developed multiple sclerosis, we were looking at the impact that potentially has on an individual in terms of their propensity to go outdoors in the daylight hours, outdoors in the sun.

MSDF

Right. So it may be the cart is before the horse in that sense; not that sun exposure is causing it, but their disability is causing less sun exposure?

Dr. Tremlett

We were looking at both sides of the equation. And I think it is important, particularly in a disease such as MS where onset of MS is a little bit fuzzy, I think, to look at sun exposure of the life course is important, and certainly our findings are indicating that. Because you want to know sunlight exposure in MS risk, but you also want to know, once someone's developed multiple sclerosis, how that influences their behavior outdoors and what implications that has if you're then trying to design the study to look at what causes MS.

You need to be really careful who you recruit, because if that person has already changed their behavior, then that may influence your findings, and you're not then actually looking at what causes MS at all, you're just looking at a consequence of the disease. So I guess that's the first part of why we wanted to do that.

And the second part is if having MS, if having a chronic condition, does influence your propensity or ability or desire to go outside, what consequence could that have for your health in terms of maybe your serum vitamin D levels or your melatonin levels, and that may have a consequence in terms of long-term health.

MSDF

You segmented people by where they were and at what ages.

Dr. Tremlett

It was pretty interesting. So, first of all, over ages 5 to 15, we found there that there was a 48% lower risk of MS for women living in high, relative to low, ambient UVB areas during their sort of childhood and early adolescent years. So that was pretty interesting. But we found, kind of to our surprise because it goes against other studies that are out there, we found that time spent outdoors in summer or winter wasn't significantly associated with MS risk in that age group, 5 to 15 years. But what we didn't realize is that it wasn't until we combined that outdoor behavior with the UVB, then we could see that there was an association. So we found that less time spent outdoors in summer in low ambient UVB areas—that was associated with a two-fold increased risk of multiple sclerosis.

That was an important step for us; I mean, it might, you know, sound obvious to combine those two, but it was an important step because other studies in smaller geographical areas such as Tasmania, or there's a study out of Norway in a small region of Norway, they can find an association between time spent outdoors in summer/winter and MS risk. But I think we couldn't find it in the US, because the US is at such a diversity of latitudes – the study spanned over 14 US states – so it wasn't until we looked at that outdoor behavior in context of ambient UVB that we could find the association.

And then, I suppose, our next step was to look at outdoor behavior over the life course. And this was really interesting, that we found some avoidance behavior was apparent in later life in multiple sclerosis. And maybe that comes as no surprise to people, but I think our numbers are interesting to put a concrete figure on it. So, for instance, by age 50, our MS cases were 60% less likely to report high relative to low outdoor exposure compared to controls, and that was in winter and in summer.

So the bottom line is people with MS, once they have MS, are not going outside as much, so they're not getting that UVB exposure, so potentially they're not making that vitamin D and serum vitamin D. And then the winter exposure's important as well, because potentially they're not getting the same melatonin production and inhibition, and that may have a really important role in terms of immunology, the circadian rhythm and your sleep cycle, which, again, all knocks back into overall health and immunology of MS. And there have been some presentations actually at this conference looking into melatonin and its association with relapses in MS, and that's pretty interesting.

MSDF

There's even some emerging thought that sleep is essential for good brain function in terms of taking out the garbage – glymphatics and things like that. So melatonin disturbances may actually have some further consequences in an inflammatory brain disease.

Dr. Tremlett

And there's some interesting studies, not that we did but others have done, looking at shift work and risk of MS. And shift work may be associated with increased risk of MS. Maybe melatonin ties into that as well.

MSDF

Is there also potentially an effect, besides on vitamin D and melatonin, that sun exposure itself has an effect on the immune system, maybe suppressing it?

Dr. Tremlett

Yeah, modulating it in some way. No, absolutely. We don't really know the mechanism. I mean, the obvious one would be sun on human skin at the right time of year on the right skin color can result in really high levels of serum vitamin D being produced. Sunlight exposure the minute it actually hits the skin surface can have a direct immunomodulatory effect. And then, obvious, sun hitting the eye. Melatonin is one of the pathways in there that may then impact the immune system.

MSDF

Is it possible to make any conclusions or even recommendations at this point?

Dr. Tremlett

No. It's an observational study, and we do actually need to do more analysis on this group of individuals. The main recommendations we could make from this study is informing how to design future studies, and also two things you could take from this in terms of recommendations.

First of all, we saw sun avoidance behavior in individuals once they've developed multiple sclerosis. That's really important because it really means that if you want to look at what is causing MS, do not take serum vitamin D levels or look at skin cancer risk, for instance, in individuals who already have MS, because they've already changed in compare to controls, adding further somehow differences are related to what causes MS, because these individuals have already changed their behavior because they've got a chronic disease. So that's the first statement, which might be a no-brainer for some people, but it's amazing how many studies are still published like that in the MS literature at the moment.

And I suppose the second piece is trying to understand if we are going to do an interventional study, what time period in an individual's life or within a population do you need to target in order to change the course and prevent the disease from occurring? And we're trying to understand that more, looking beyond the window age 5 to 15, look more into adulthood to see if ambient UVB is associated with MS risk later in life and into adulthood. And others have shown that there does seem to be an association even into adulthood, which is exciting because if you do want to do an intervention study, then you haven't necessarily missed the boat because you've not intervened during childhood. But, I mean, the real question is how do you intervene and what with? And that's another topic in itself.

MSDF

We'll leave that for another day. Thank you.

Dr. Tremlett

Thank you very much.

[transition music]

Next week, we'll continue our discussion with Professor Tremlett when she'll talk about her preliminary studies on pediatric MS patients and their gut microbiomes.

Until then, thank you for listening to Episode Sixty-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 Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. 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.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[outro music]

Transcript will be available Thursday, 24 Dec

[intro music]

Host – Dan Keller

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

In this podcast, Dr. Yanming Wang of Case Western Reserve University in Cleveland, Ohio, discusses a solution to the vexing problem of how to track changes in myelin in the brain and spinal cord, a measurement believed to be especially important for new candidate drugs to restore this insulating sheathing around axons.

First, here are some new items in the MS Discovery Forum.

A new data visualization showcases the collaborations among authors who published papers reporting the results of clinical trials in progressive forms of multiple sclerosis in the last 30 years. You can find the network map on msdiscovery.org under “Research Resources.” You can mouse over circles in the graphic to find researchers' names. Click and drag the circles to animate the map and reveal connections.

In research news, a Swedish team took the first steps toward finding potential disease markers in the immune cells of asymptomatic people with MS and with seasonal allergies. The study pinpointed three key proteins that may transform normally protective T cells into ones that attack myelin in the case of MS. The three proteins are transcription factors, which glom on to DNA and control which genes turn on and off. According to data from genome studies, the proteins are more common in genetic regions associated with disease, strengthening the case for their role in MS. Finally, the three proteins act differently in people with immune-related diseases, including multiple sclerosis, according to tests on blood samples. Ultimately, the researchers want to learn if they can detect multiple sclerosis and other autoimmune conditions much earlier.

[transition music]

And now to our interview. MSDF caught up with Dr. Yanming Wang last month at the 2015 World Congress of Neurology meeting in Santiago, Chile. We discussed his solution to what has been a missing link in MS research and practice; that is, how to image myelin -- not just lesions on an MRI, but how to tag the substance itself using a biomarker for molecular imaging called M-E-D-A-S, or "mee-das." Going beyond diagnosis, Dr. Wang told us it may eventually allow clinicians to get a better handle on disease progression and efficacy of treatments.

Interviewer – Dan Keller

You had referred to molecular imaging of myelin as the missing link. Why is this the missing link?

Interviewee – Yanming Wang

Because molecular imaging has really transformed how we practice medicine today, and it has become a standard care for virtually many neurological diseases. However, in multiple sclerosis, there's still no effective imaging technique in place that can help physicians to monitor not just for diagnosis, but also to monitor the disease progression.

MSDF

And would this be useful also in monitoring potential therapies?

Dr. Wang

Exactly. There's a lack of imaging technique that allow people to monitor the drug efficacy, particularly for those drugs that try to repair the myelin damage in the CNS.

MSDF

How would this differ from MRI imaging, what you see there, versus having a radioactive biomarker?

Dr. Wang

Currently, MRI is the commonly used imaging modality in MS, however MRI provides only anatomical information and also detect brain lesions. However, those lesions detected on MRI are not specific for myelin pathology.

MSDF

You do have a compound now, [11C]MeDAS, which would be specific for myelin. Is that right, is it very specific for myelin?

Dr. Wang

Exactly. It's very specific for myelin, because the advantage it has over MRI is that that is truly a molecular imaging modality which uses myelin-specific radiotracers that allow to quantitatively monitor the myelin damage and myelin distribution in the brain. So for this reason, we developed a specific radiotracer that can selectively bind to myelin with high affinity, so that we could directly image the myelin distribution.

MSDF

How quickly does it reach the CNS and you can image?

Dr. Wang

It takes minutes, literally, for the radiotracer to penetrate the BBB and enter the brain, and then the whole process takes only 60 minutes.

MSDF

Can you briefly describe your rat model where you're using lysolecithin as an MS model, and then what you did with your marker?

Dr. Wang

Lysolecithin model is an established model of focal demyelination in the brain, so we used that model to test our compounds to monitor the demyelination and remyelination. So after injection of MeDAS, the compounds could readily enter the brain and selectively bind to the myelin. And then at the peak of the disease, which is a peak of the demyelination, the brain uptake of the compounds is lowest, versus when the brain is recovered, then the brain uptake of the compounds is increased. So this demonstrated the in vivo specificity of the radiotracer for myelin.

MSDF

And you can image myelin on the way down and on the way up; you have this hepatocyte growth factor which causes some remyelination?

Dr. Wang

Right, exactly. In collaboration with my colleague, Bob Miller. So we'd use this imaging modality to see if we can monitor the drug efficacy for remyelination. So we'd give this HGF, which is a growth factor that promotes remyelination, and then we could use this imaging technique just to monitor the increase of remyelination after the drug treatment.

MSDF

Everything right now is in animals. Do you have plans for any human trials?

Dr. Wang

Yes, we are working on this paperwork required by FDA to put these compounds in humans.

MSDF

Is the compound so far nontoxic; it's diamino stilbene, is that right? Does it have any estrogenic effects or other toxic effects?

Dr. Wang

No. We have done systematic toxicity studies and there's any adverse effects in animal models so far.

MSDF

What do you see as the clinical utility of this if it enters the human realm?

Dr. Wang

It's going to be a very powerful tool for diagnosis and prognosis, and also particularly for evaluation of drug efficacy. As you know, currently pharmaceutical companies and academic investigators are all trying to develop new drugs that can repair myelin damage in order to restore the biological functions. However, there's a lack of imaging tools in place that allow them to monitor such myelin repair therapies, and this could provide the missing link for this endeavor.

MSDF

Does PET imaging with this compound correlate at all with what's seen on MRI, especially in a kinetic sense following time course?

Dr. Wang

Well, yes. In the wonderful publication in Annual Neurology a couple years ago, we did demonstrate that this PET imaging technique can be used as an imaging marker that correlates with the disease progression in terms of the severity of the symptoms in animal models, in the EAE models. The EAE rat, for example, its appearance, the relapsing or remitting stage, and that we could use this imaging marker to correlate nicely with the symptoms. And this is one of important application if we put this into clinical use.

MSDF

Is this compound the end-all and be-all, or are you developing others, or have some gone by the wayside for various reasons?

Dr. Wang

This compound, and also this imaging technique, could be used not just only in MS, but can also be used in many other neurological diseases, such as Alzheimer's disease, spinal cord injury, and stroke, for example, because all of these neurological diseases are associated to some degree with the myelin damage.

MSDF

Have we missed anything important, anything to add?

Dr. Wang

Again, I think the imaging technique, particularly molecular imaging technique based on positron emission tomography, is lagged behind in the field of neurological diseases because of the complexities of the brain and the lack of molecular probes that could advance our understanding, also facilitate the drug discovery.

MSDF

I appreciate it. Thank you.

Dr. Wang

Oh, thank you very much then.

[transition music]

MSDF

Thank you for listening to Episode Sixty-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 Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. 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.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[outro music]

Transcript will be available Tuesday, 17 November 2015

[intro music]

 Host – Dan Keller

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

In our previous podcast, you heard about a group of leading MS researchers and clinicians calling for a big change in improving care for people with MS. The new report, called Brain Health – Time Matters in MS, makes the case for a therapeutic strategy to minimize disease activity. The report advises early diagnosis and treatment, and regular monitoring of disease activity. The report urges patients, physicians, health care payers, and policy makers to support the goal of life-long brain health.

In this podcast, another one of the report authors, Dr. Helmut Butzkueven, talks about what the new treatment target means for patients and their doctors in the real world.

This is one of our extra podcasts from the big MS meeting in Barcelona talking about ways that evidence from research can be translated now into better MS outcomes

But first, here are some new items in the MS Discovery Forum.

Every week, MSDF lists the latest scientific papers on MS and related disorders, with links to the abstracts on PubMed. Of more than 110 new studies published last week, we selected three as editor’s picks.

MS has been traditionally viewed as a T cell–driven disease, but a new paper from Canadian researchers introduces another villain—a rogue type of B cell in people with MS that may fuel inflammation in two ways. This may be why general B cell depletion seems to work so well in MS and may lead to more targeted treatments.

In a new twist on dietary fat and autoimmune disease, German researchers report that certain fats work through gut microbes to exert both good and bad effects. In mice, they found certain fats were protective against inflammatory fats. They have moved on to testing in healthy humans and hope to study the impact in people with MS.

A cost-effectiveness study from Spain says do not judge a drug by its price alone. Glatiramer acetate may be more expensive than interferon-beta, but fewer relapses and reduced spasticity may make it more cost effective. Interesting, but you can be sure this fuller economic look will not be the last word on drug costs.

[transition music]

And now to our interview with Dr. Helmut Butzkueven, who directs the MS services at the Royal Melbourne Hospital and the Box Hill Hospital in Melbourne, Australia. We spoke with him at the recent European Committee for Treatment and Research in MS, or ECTRIMS, meeting in Barcelona about the Brain Health report that was launched at the meeting. The main thrust of the report – aimed at the broad MS community – is that time matters in MS. The report lays out several goals to maximize brain health over the lifetime. A critical one is early intervention.

Interviewee – Helmut Butzkueven

We know that early disease activity sets up long-term problems. However, early disease activity is often relatively silent to the eye. It’s not silent to the eye of the MRI machine and other monitoring tools that we have. So we would like clinicians and patients, not actually just in early disease, but starting right from the start to have a proactive monitoring approach to jointly assess their disease activity and take action if things are not going well.

Interviewer – Dan Keller

How much of an emergency is it? If someone finds out they have a cancer diagnosis, they rush to a surgeon, oftentimes. If they find out they have high cholesterol, they might take a year or two to decide to get on a statin. So what’s the time frame we’re talking about here?

Dr. Butzkueven

I think the appropriate time frame to think about is months, actually. We think that an MRI scan should be performed approximately every 12 months to assess disease activity, to assess how your current treatment is performing. So it’s not seconds or minutes; thankfully, multiple sclerosis isn’t exactly like an acute stroke or a heart attack. But it’s also not a time, particularly early in the disease when you could be setting up these kind of strategies, to just leave people be. We need to, when we first see patients, articulate our monitoring goals.

MSDF

And how quickly should someone, when they’re referred and there’s a putative diagnosis, get that scan initially?

Dr. Butzkueven

As soon as possible. I mean, scans are crucial, obviously, for diagnosis – accurate diagnosis, as well as for setting up the monitoring phase, because the first scan can then be compared to the next scan, and so on.

MSDF

What other goals are there for treatment and management?

Dr. Butzkueven

The key things that we want to really focus on, apart from what we’ve already discussed which is early diagnosis and articulating a treatment and monitoring plan to maximize brain health, is a joint approach. So for people with MS and doctors to both be empowered to jointly manage the disease. So this includes, of course, increasing consultation time, giving people time to discuss their MS with their managing team. I think this kind of move away from paternalistic medicine, to empowering patients to be part of the management process to self-manage is hugely important. That’s just in step with the modern world.

The other thing is more indirect. Across the world, we face huge differences in access to disease-modifying drugs. Some of us living in the United States and Australia in Germany, Switzerland are luckier than others. And we really need to provide evidence to government that disease-modifying drugs are worth funding.

MSDF

Or else what happens?

Dr. Butzkueven

Else people, and ultimately governments, incur the costs of markedly worse disability.

MSDF

To empower patients takes certain knowledge and, I suppose, permissions or rapport with the physician. And to empower the physician, I suppose, takes knowledge, evidence, consult. So are these two different things? Do they move in parallel, but they require different activity?

Dr. Butzkueven

Yes, they do. Of course they do. To some extent, changing practice in an interaction can come from either side of the interacting party, but certainly patients, on the whole, probably need to be more demanding. They need to have access to evidence, and I’m going to say something controversial, to actually help assess the clinical care that they are receiving. So people should say, for example, if this report, the evidence suggests that perhaps we should be doing something else. What do you think?

Physicians, as I said, need to be strongly encouraged to have a priori a specific plan. If you were someone with MS, and we saw you for the first time in our clinic, we should be telling you what the goals are. We should be telling you what our scheme of monitoring is going to be to maximize your outcome, to maximize your brain health.

MSDF

What kind of a role can longitudinal databases play in changing policy?

Dr. Butzkueven

They’re really the only source of long-term data. MS is a disease which you’re going to have for decades, once you’re diagnosed with it, and it likely will cause you and your government very significant costs over that time. But those costs can only be measured if we measure those outcomes, and the only way to really measure them is longitudinally. So databases embedded in the real-world healthcare collecting just a minimum of information on as many MS patients as possible can be enormously powerful, doing the sums in the first place, actually understanding how much disability there is; how much can be prevented with appropriate treatment strategies; and, dare I say it, how much money government could save.

MSDF

MRIs are now a powerful tool. Other medical specialties have had all sorts of invasive measures in the past. You could take biopsies of skin, breast, prostate, liver. You never had an assessment tool this powerful, but now this one is fairly noninvasive. It’s completely noninvasive. What can it tell you? I mean, people look for lesions, but there’s much more to be derived.

Dr. Butzkueven

Yes, of course. Lesions is still a key outcome, but the other thing is brain shrinkage – brain atrophy. So we, increasingly, understand that people who are experiencing significant brain loss – brain tissue loss – early in their MS will do worse, in the long-term. So here we have another target for monitoring. And people might say, well, I do an MRI scan, but there are no lesion changes reported. There’s no volume changes reported. But this world is changing rapidly. Image recognition analysis tools are advancing very quickly. I predict, within two or three years, routine MRI will actually spit out these metrics for us. At the moment, a lot of reporting, unfortunately, in the world is still what we would call qualitative rather than quantitative. But we’re going to start seeing those numbers, and we need to be ready to act on them.

MSDF

How much faster does the brain, in an MS patient without treatment, atrophy or lose volume compared to an age-matched control?

Dr. Butzkueven

So this is a question that I can answer in two ways, I think, to illustrate the concept. I could say it’s five to seven times faster. What I’m talking about there is averages, medians if you like. What I should be saying is that it could be anything. Your trajectory, as an MS patient, could be exactly within the normal range, I mean, sadly – particularly over the age of 30 – all of us lose a bit of brain volume a year: 0.3%, 0.4%. In MS, that could be your trajectory, and that would be fantastic. On the other hand, you could the person losing 3%, 4% – 10 times, 15 times normal. And we could pick that within a year or two, and that is the time to intervene, not when that ultimately results five, six, ten years later in progressive disease.

MSDF

You’ve made the analogy of managing MS to a new car and its warranty. Can you tell me about that?

Dr. Butzkueven

I was really just trying to say that plans for keeping things well, keeping things in shape, are quite prominent in society. So this analogy is simple. You buy a new car. What you get with it is a service book. The service book gives you a plan for managing your car. At 6 months, there’ll be a little tire change, oil change; 12 months there’ll be a major service, and so on. And the thing is, as a customer, I mean, you buy the car. It’s already there. It’s the same thing. We want clinicians and patients to demand and to deliver a plan. This is how we’re going monitor your MS to maximize the health of your brain.

MSDF

So this is your 6 month service. This is your 12 month service.

Dr. Butzkueven

Exactly. So, for example, in might be we will see you every 6 months, and we’ll do a neurological examination. We might do a particular cognitive test. We will do a repeat MRI scan, ideally on the same machine, once a year. We will be looking for the following: we will take action if things are going badly. If things are going well, then we’re reassured. But we need people with MS to demand this, and we need clinicians to deliver these plans.

MSDF

I don’t mean to make light of the situation of having the disease, but I think people respond well to something they already know, like a service plan.

Dr. Butzkueven

Yes, sure. I guess that’s why I’m using that analogy. Maybe we should say we need a service plan for MS.

MSDF

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

Dr. Butzkueven

Nothing. We’ve covered the key recommendations of the report: access to early diagnosis, consideration of early treatment, a service plan, empowerment of people with MS to actually have accurate information, and being empowered in shared decision-making, and finally, the health economics situation, powered by clinicians – more and more clinicians – collecting long-term outcomes data on people with MS.

MSDF

And the Brain Health report is freely available, and we will link to it. I appreciate it. Thank you.

Dr. Butzkueven

It’s a pleasure. Thank you for talking with me.

[transition music]

MSDF

Thank you for listening to Episode Fifty-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 Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. 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.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[outro music]

[intro music]

Host – Dan Keller

Hello, and welcome to Episode 58 of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

A group of people are calling for a big change in improving care for people with MS. There may be no cure for MS yet, but there are a lot of ways to improve their outcomes. In this podcast, one of the ringleaders, Dr. Gavin Giovannoni, talks about a new push to use long-term brain health as a goal in MS treatment.

The new report, called Brain Health, makes the point that time matters in MS. The authors draw on more than 300 research studies to show evidence that brain tissue can be preserved with early and effective treatment, and regular monitoring of disease activity. The report urges patients, physicians, health care payers, and policy makers to support the goal of life-long brain health.

This podcast gives you the main take-home points from the Brain Health initiative, launched at the recent MS meeting in Barcelona, Spain. We will have extra podcasts for you in the coming weeks about other ways that evidence from research can be translated now into better MS outcomes.

But first, here are some new items in the MS Discovery Forum.

In the discussion section, a team of graduate students wants to hear from people with MS and their families. The team is from Santa Clara University, located in the heart of Silicon Valley in California. They have a class project to design a software product to assist people impacted by MS. Help them out by completing their survey.

Coming up on our meetings and events list is next week’s World Congress of Neurology in Santiago, Chile. MSDF will be there gathering new podcast interviews. If you, too, will be at the conference and would like to meet with us – or if you’re interested in being interviewed about your research for a future podcast – please email us at editor@msdiscovery.org.

The meeting list includes many specialty conferences and seminars of all the different kinds of scientific expertise that goes into understanding MS, from immunology to myelin biology, genetics, and brain and spinal cord imaging. Please add your meetings, workshops, and seminars. This is just one of the ways that MSDF shares information across the many different specialty areas to advance treatments for MS. Help us by adding other MS-research-related events. It’s free to post.

Our Drug-Development Pipeline contains 44 investigational and approved agents for MS. Last week, we added results from one new trial, we updated subject matter from four other trials, and we added eight other pieces of information to the database. One update summarizes findings gathered from a 15-year follow-up visit for participants in the PRISMS interferon beta-1a trial.

[transition music]

And now to our interview with Dr. Gavin Giovannoni, head of neurology at Barts and The London School of Medicine and Dentistry in the U.K. We spoke with him at the recent European Committee for Treatment and Research in MS, or ECTRIMS, meeting in Barcelona about the Brain Health report that was launched at the meeting. The main thrust of the report – aimed at a broad audience of MS community members – is that time matters in MS.

Interviewer – Dan Keller

In terms of the Brain Health report, can you give me a broad overview of what the intent was and what you hope to accomplish?

Interviewee – Gavin Giovannoni

I mean, the real issue is to try to raise awareness and use it as a platform for trying to get policy changed. And the target audience is just the MS community, as well as health care providers, payers, politicians, etc. And one of the things we’re beginning to realize now as we have more effective therapies, and we begin to learn more about MS, is that we are compromising the health of our patients by not treating them quickly enough or manage them quickly enough. I mean, there are large delays in patients being diagnosed, getting access to treatment, and when they’re on treatment, they’re not being monitored actively.

And there’s now emerging data that if you’re on a therapy, and you’ve got ongoing disease activity, you don’t do very well in the long-term. So the idea is to try and encourage people to treat to a target, monitor, and escalate rapidly. So it’s really trying not to waste time, too, essentially. And we borrow the term, “Time is Brain” from “Time Matters” from the stroke, where we know that, you know, every minute counts. And we would like to get the attitude across to people who are treating MS that every week, every month counts.

MSDF

At the initial diagnosis, how quickly should things move along, scanning, treatment?

Dr. Giovannoni

I mean, we’ve got guidelines within our socialist healthcare system, the NHS, to get the diagnostic phase over with in a four-week period. If you’ve got the disease, it’s very anxiety-inducing, the whole process. In reality, you’d like to get it over with in days. And then you need to start the counseling and education process. And I think you can’t rush people onto therapy within days because the holistic approach is people got to understand their disease, the implications of the illness, the prognosis. They’ve got to come to terms with it as well before you can actually start discussing the implications of therapy, which may be life-long. So I’m not talking about this is like stroke – you have that thirteen minutes – I think you need to try and shorten the whole process and be active about it, not be passive.

Most clinicians in the world now just monitor their patients clinically. They don’t monitor them with MRI scans. They just wait for them to break through. Sometimes they accept minor relapses as just being part of the disease, and I think now that we’ve got more effective therapies, we shouldn’t be accepting any breakthrough activity. We should be escalating people to more effective therapies. And the data is becoming really strong that active disease, in the form of relapses or MRI activity, does portend a poor prognosis, so you want to switch it off.

MSDF

The report laid out some specific goals. Can you delineate some of those?

Dr. Giovannoni

The main goal is speeding up the whole process, so a rapid diagnosis, rapid initiation of treatment, monitoring, rapid escalation or possibly even flipping the pyramid – if they’ve got a bad prognostic profile, give the more effective therapies. Also, collect data so by monitoring, you hopefully will change behavior. And then the other thing that’s hidden is the cost effectiveness of these treatments. So, we need to make systems available to provide these drugs at cost effective prices, particularly in countries that are resource poor. It’s fine talking about North America and Europe – relatively wealthy areas of the world – where we have insurance systems to pay for these expensive new emerging therapies. But if you just to any of the developing countries, people with the disease don’t have access to disease-modifying treatments. We’re just letting the disease run its natural course, and I find that very upsetting.

There’s a whole literature and emerging dataset on brain health from, mainly, the dementia – Alzheimer's field – and some of it’s applicable to MS: getting patients to stop smoking; they must exercise regularly, try to avoid drugs that affect cognition, avoid excessive alcohol, sleep properly. Comorbidities must be managed actively. By that I mean hypertension, diabetes, etc. So there’s all that lifestyle, comorbidity issues that also need to be focused on. It’s basically making neurologists and healthcare professionals aware that there’s more to the brain in MS than just inflammation. We need to think of it holistically and take it seriously.

MSDF

What do you see as some of the barriers to implementing all these things that you’re recommending?

Dr. Giovannoni

The barriers I wish I could answer it easily. I mean, we know that there’s slow adoption of innovation. Certain fields are more slow at adopting innovation than others, and I think neurologists, intrinsically, are quite conservative. And up until we had therapies in MS, we were just diagnosticians and giving prognoses. Now that we’ve got treatments, we need to adapt to the fact that we’ve got therapies that can make a difference to people with MS. So the slow adoption is attitude, culture, and regulatory hurdles. There’s cost hurdles. Health insurance companies don’t pay for our monitoring, in large parts of the world, so you’re going to have to fight with them to be able to monitor with MRI scans. Patients themselves – try and nudge them to stop smoking and eat properly and exercise. It’s easier said than done. I mean, this is a global population issue, and you know, why should people with MS be any different to the general population. So it’s not easy. We need to think creatively about how we get this done.

MSDF

But it sounds like nihilism should be passé, if in the past, all you could do was diagnose and hope for the best. Now that’s really not the situation.

Dr. Giovannoni

Yes, but I think there’s another form of nihilism. And so in the past, we had therapeutic nihilism where we didn’t give any therapies. I think we’ve got a form of subliminal nihilism in the sense; we put people on less effective therapies. We’re not monitoring them, but their disease remains active. I call it smoldering MS. Unless we monitor with sensitive MRI techniques, possibly other monitoring, we’re not picking up the smoldering MS. And so I think we’re potentially leaving a whole generation of people with smoldering MS to obviously a better outcome than they would have had with no therapy, but not as good an outcome if they would be as connected to more effective therapies.

So that the subliminal nihilism, I just thought about that term, it kind of captures what I’m trying to, because, you know, what we see affects behavior. If we don’t see it, we don’t change our behavior. So part of this report is to make people observe, measure, monitor. And if they see activity, hopefully, it’ll change their behavior.

MSDF

In so many specialties, people say, well, I don’t treat lab values. I don’t treat images. I treat patients. But in this case, it seems like you do intervene when there is an imaging change.

Dr. Giovannoni

Yes, because we now have data, so this has got to be evidence-driven. And we’re not saying every recommendation in the policy report’s got unclad evidence about it. There is some weakness in the evidence base, but we think the evidence base is strong enough to make the recommendations. And we’ve actually put into the report that where there isn’t enough evidence, we need to generate more evidence. And to be honest with you, we need a population study comparing people managed with routine care versus patients treated to target with rapid escalation. MSBase has kind of done that without the MRI monitoring, because they don’t have MRI data in their database. They’re just looking at the clinical, letting people break through with relapses versus relapse-free, in those that are rendered activity-free clinically, do much, much better. And I think that tells us that if we were using MRI, it will even be better. So at least we know that MRI activity is a surrogate for relapses.

And there’s also scientific principle. We know, under the microscope, inflammatory lesions are not benign. They’re associated with transected axons, neuronal loss, etc. So it’s hard to deny the scientific principle of allowing lesions to continue to be active. To me it makes no biological sense. And this is not new. We’re just stealing the ideas from rheumatology and nephrology. They treat to target. They try and suppress inflammation as much as possible, and they’ve had incredible success. And they didn’t do it from an evidence base; they did it from a scientific principle.

And, as they collected their data in registries, they confirmed what the science showed. Long-term follow-up with these patients has shown that if you treat to target in rheumatoid arthritis and with rapid escalation, you protect joints. And joint replacements now in rheumatoid patients has plummeted by more than 80 percent.

I think our metric will have to be walking sticks and wheelchairs. We’ll see the use of walking sticks and wheelchairs plummet. Maybe employment – that’s the other thing we’re trying to highlight is most of the early disability in MS is not physical, it’s cognitive. And the early unemployment rates that occur before people become physically disabled are driven by cognitive problems which manifest as cognitive fatigue. So, you know, what we’re trying to do is also shift people’s attention away from just physical disability and think about cognition, which is an early disability. And hopefully, if we can treat people as early as possible, we’ll protect their cognition and allow them to continue working. So maybe the metric should be employment, as one of the metrics.

MSDF

So many reports in all areas come out and they’re sort of one-shot deals. Do you have a plan for giving this thing legs so that it’s not just buried once it came out?

Dr. Giovannoni

Yes, so we’ve got a whole lot of initiatives following on this. We’ve put together a grant application package. We’ve got a dissemination plan, both at a regional and international level. We’ll also want it connected to audit tools, so provide some audit tools where you can actually audit—measure—what we’re trying to achieve and, hopefully, use that as a quality metric. We think we if can start measuring, people will change their behavior. We also want to create an audit tool for people with MS to audit their own service. So in other words, they will go in and say, am I being monitored? How am I being monitored, just clinically or with MRI? And ask the right questions, and, hopefully, activating patients to ask their clinicians to be monitored may also change behavior.

We don’t want it to be a name and shame type thing. We want it to be a positive thing, by measuring, we’ll change behavior, so that’s what we want to do. The only thing, though, it can’t be done quickly. We need to get buy in from the whole community, so we’ll have to have an engagement program to get there. Get a competition going, international competition where people can provide creative ideas to try and help with viral dissemination. So get an infographic or a movie or a play or a book or a poem, something that can go viral. And then we’re going to, hopefully, have funding to update the report.

We are going to have a very active website where people can download the report. And we’re going to try and create content around Brain Health. Another thing we’re going to be doing is looking for funding to translate it into other languages. We’ve already had requests from several non-English speaking nations for translations. So the Dutch want it translated. South America wants it in Spanish. We’ve had a request from the Japanese, Russians. And so if we can get it translated, we’re probably not going to get the whole document translated. We’re going to make executive summaries, one for patient focused, one for clinicians, one for policy makers. And we’ll, hopefully, get those translated into multiple languages.

MSDF

MSDF will put the link on the site so that people can access it in English now. Is there anything to add or we’ve missed?

Dr. Giovannoni

I think we’ve got to start changing the behavior of neurologists in the sense that we need to make them think of their responsibility for looking after people with MS’s brains. We tend to focus on making them relapse free. If we actually shifted the target away from being relapse free but maintaining brain health, so these people can age as normally as possible – we’re not trying to say that people with MS will age normally, but we need our brains for when we get older. So if they start taking responsibility for the holistic management of MS, I think we’ll get the momentum going where people will be much more actively managing MS.

[transition music]

MSDF

Thank you for listening to Episode 58 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 Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. 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.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[outro music]

[intro music]

Host – Dan Keller

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

This week’s podcast comes to you from last week’s big MS meeting in Barcelona, Spain, with an interview with Dr. Timothy Vollmer, who gives his take on the early results of a large Phase 3 study of ocrelizumab for primary progressive MS. The experimental drug blocks circulating B cells.

We will have several extra meeting-related podcasts for you in the next two weeks. In the next one, Dr. Gavin Giovannoni talks about a new push to use long term brain health as a goal in MS treatment. And Dr. Vollmer will return in the coming weeks to discuss the Denver treatment experience with another B cell blocking drug, rituximab. But first, here are some new items in the MS Discovery Forum.

Every week MSDF lists the latest scientific papers related to MS with links to the abstracts on PubMed. Of nearly 100 new studies published last week, we selected three as editor’s picks.

Two of our editor’s picks come from a larger collection on MS in JAMA Neurology. One study reports on an equivalence clinical trial comparing a generic glatiramer acetate, Synthon, with Copaxone, the branded glatiramer acetate, for relapsing remitting MS. A global team of investigators found equivalent efficacy, safety, and tolerability in the randomized, controlled trial. The findings provide reassurance about well-made generics for patients and neurologists, say other researchers in an editorial. But the whole idea of generics is to make a dent in the skyrocketing costs of MS drugs, and the generic is priced at $63,000 a year instead of $65,000 and $74,000 for the two versions of the branded drug.

Another paper in the same JAMA Neurology checked to see what the vitamin D levels of nearly 1500 people treated with interferon beta-1B might say about the course of their disease. Higher vitamin D levels were associated with fewer new active lesions in the mostly white, mostly female patients with relapsing remitting MS, but there was no correlation with clinical disability or brain atrophy.

Our third editor’s pick is a paper investigating the cancer risk from cladribine compared to other MS disease modifying treatments. A large Phase 3 study showed the experimental drug to be highly effective in relapsing remitting MS, with nearly half of patients showing no evidence of disease activity after two years and two courses of the treatment. But it was refused a license by the European Medicines Agency in 2013. Now, based on their new meta-analysis of eleven studies, the authors say they cannot confirm nor deny a cancer risk, and that cladribine should be investigated further as an MS therapy.

Our drug development pipeline contains 44 investigational and approved agents for MS. Last week, we added results from two new trials, we updated information from 16 other trials, and we added 20 other pieces of information. Trial updates include findings about ocrelizumab’s ability to reduce relapses and minocycline’s capacity to reduce the risk of conversion to MS after an initial demyelinating event.

[transition music]

And now to our interview with Dr. Timothy Vollmer, Professor of Neurology and Medical Director of the Rocky Mountain MS Center at the University of Colorado in Denver. When we met at the European Committee for Treatment and Research in MS, or ECTRIMS, meeting in Barcelona, Dr. Vollmer laid out how results of the ORATORIO trial of ocrelizumab shed light on two hypotheses of what goes wrong in primary progressive MS, and which one is most likely.

Interviewee – Timothy Vollmer

There currently are two hypotheses for what drives primary progressive disease. One is that it’s like relapsing disease, and it’s driven by inflammation. And the other one is that it’s a noninflammatory disease that’s being driven by neurodegeneration and has a separate biology. Now that we have positive results from the ORATORIO study, which is a study of ocrelizumab which is an anti-CD20 monoclonal antibody that deletes B lymphocytes from circulation, given that this is the very first time we’ve ever succeeded, it’s telling us very important thing, and that is: inflammation does drive primary progressive MS.

And the other important message from here is that this study studied a significantly younger patient population with primary progressive MS than all the other studies. The mean age was around 44. The reason that’s important is because, epidemiologically, we see a decrease in inflammatory activity as a function of age, and older patients often don’t express any evidence of that. And so far, in all the primary progressive studies, especially the OLYMPUS trial, those patient populations don’t respond to anything. So it’s telling us that we can treat primary progressive MS, but you’ve got to start early.

Interviewer – Dan Keller

That seems to be the message overall in MS, in general, though.

Dr. Vollmer

Yes it is. And the reason is, is because MS results in an accelerated brain volume loss, and brain volume loss is going to translate into disability, at some point, for almost everybody. Maintaining brain volume so that you can age normally late in life is a critical goal, not just in MS, but in other neurological diseases.

MSDF

Does that brain volume loss or other changes in the brain relate to really the onset of the progressive phase?

Dr. Vollmer

The answer is yes and no. From a statistical standpoint, it’s very hard to sort of identify a specific point in the process of brain volume loss that you can say, okay, they’re going to transition into progressive disease. That’s probably due to the fact that the mechanisms that underlie reserve capacity in brains may vary a little bit from patient to patient, and that they have different capacity to compensate for this injury. The other complication is that MS, as a multifocal disease, is not necessarily distributed evenly throughout the nervous system, though. In some patients, they have a relatively small amount of disease, but it’s in the neck, and they’re still highly disabled. And because of that very complicated pattern for it, it is hard just to use one global measure to predict how patients are going to be from a disability standpoint.

MSDF

Do the results of the ORATORIO study give us more confidence in pursuing the B cell as an important effector in MS?

Dr. Vollmer

Absolutely. The converging data, now, both in progressive forms and in relapsing forms, says the B cell is playing a critical role. There are CD20-positive T cells, and so there’s still some discussion whether the drug may be having an effect on those, but in the most recent reports, it does decrease those with first administration, but then they recover very quickly. And at subsequent administrations of the anti-CD20, they’re not deleted. So that pattern suggests to me it’s not an effect on T cells, it’s an effect on B cells which remain suppressed for months after a single injection.

MSDF

CD20 is on B cells but, as I understand, not on plasmablasts or plasma cells. So what is the relative contribution of B cell biology versus just antibody?

Dr. Vollmer

A major difference is that plasmablasts and plasma cells are not very good antigen presenting cells. Whereas, B cells, if they can engage the antigen that their B cell receptor is targeted for, become extremely effective antigen presenting cells: the most effective antigen presenting cells in the body. And they can be about ten thousand times more effective that dendritic cells or macrophages. So that’s why I think that, given the fact that the most effective therapies we’ve currently studied right now are all B cell based therapies, I think it’s telling us is that the B cell is playing that critical role, and most likely, that is in both cytokine release and in antigen presentation in the brain.

MSDF

From the ORATORIO study, what more do you want to see? The data is just coming out, and they’re going to do a bunch of analyses. What sort of things should they be looking at?

Dr. Vollmer

Well, they have a number of other clinical measures, and I believe they also have some patient reported outcomes, so I’d be very interested to see if the patients actually perceive a benefit as measured by those PROs. They have the timed twenty-five foot walk out, which they reached and was statistically significant. They had sustained disability progression at both three and six months which was statistically significant. And they reported brain volume loss was decreased in the ocrelizumab treated patients and was statistically significant. We would like to know more about the inflammatory markers in the patients and the correlation between having baseline evidence of disease activity, such as a gadolinium enhancing lesion, and the probability of response to therapy.

MSDF

What about the time course of response to the therapy? It seems like it’s more rapid than you would expect if an insult sometime in the past led to what you see today. But the ocrelizumab results seem to be on a faster track than that.

Dr. Vollmer

Well, the reason I believe that is, is because, as I said before, they really pushed down the median age in their population to much younger patients. And again, in long term studies that have looked at gadolinium enhancing disease activity, we do see it in primary progressive disease. So it’s not true, in my view, that primary progressive MS patients have a different MRI pattern. In studies that actually controlled for observer bias, where the neurologist didn’t have a chance to look with an MRI scan, but made the decision whether it was progressive or not progressive disease based on clinical history, which is the only way that we really can do it, then the previously reported biases of having nonspecific noninflammatory MRIs disappears. And that paper was published about six years ago.

So, I think that we have a lot of built in biases, as a field, when you think about MS, and, unfortunately, those biases are often not supported by objective data. And yet, they do make their way into the literature, mainly because they don’t control for age. And when comparing progressive patients, relapsing patients, or primary progressive patients to relapsing patients the fundamental difference is progressive patients tend to be 10 to 15 years older on average than the relapsing patients they’re comparing them to. And it’s that age difference that explains most of the differences that people talk about. It’s not the fact they have a different form of the disease.

MSDF

Anything else to add on this that we’ve missed?

Dr. Vollmer

As I said, we need to get subset analysis out of the ORATORIO study to see just which age group and demographic the patients really got the most benefit. My suspicion is we’re going to again find it’s the younger patients that show the biggest effect, again emphasizing that starting early in the disease with therapy is a key issue. And, again, I think it’s going to argue that you need to use highly effective therapies as early as possible, in order to get the best effect.

MSDF

Very good, thank you.

Dr. Vollmer

Thank you.

[transition music]

MSDF

Thank you for listening to Episode Fifty-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 Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdicovery.org is part of the nonprofit Accelerated Cure Project for multiple sclerosis. Robert McBurney is our President and CEO, and Holly 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 a comments, criticisms, and suggestions to editor@msdiscovery.org.

For Multiple Sclerosis Discovery, I’m Dan Keller.

[outro music]

 

Transcript

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Fifty-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. Gavin Giovannoni who discusses the first experimental drug to show some benefit in a progressive form of multiple sclerosis in a major trial. The drug is ocrelizumab, and the trial is called ORATORIO. But first, here are some new items in the MS Discovery Forum.

The ocrelizumab findings were the big news at last week’s large international MS meeting in Barcelona, Spain. Our Research Roundup highlights other breaking stories from the meeting. Stay tuned for more in the days to come. We’ll be rolling out in-depth stories on some research themes we followed at the meeting. And we will have some extra meeting-related podcasts for you in the next two weeks.

Every week, MSDF lists the latest scientific papers related to MS, with links to the abstracts on PubMed. Of 138 new studies published last week, we selected three as editor’s picks.

In one study, a British team found a new reason why remyelination fails in disease. When damaged axons lose their myelin sheath, as in multiple sclerosis, they strike up a conversation with immature myelin-making cells. The axons reach out with new synapses to order the cells to grow up and make new myelin. If axons can’t call for help, as also may happen in MS, the myelin-making cells cannot respond. The team made their discovery in rat brains. They also found new synapses and telltale signaling molecules in postmortem brain lesion samples from people with MS.

In another paper, a Spanish group looked at other factors that may block the brain’s ability to repair itself after inflammatory damage. A pair of molecules, known as semaphorins, may block myelin-making cells from coming to the rescue of damaged axons. The findings come from human tissue samples and may hold promise as targets for future treatment.

Our third editor’s pick paper looks at factors influencing the intention to exercise and the execution of exercise among people with multiple sclerosis. A Danish team did an extensive review of rehabilitation and sports medicine literature. They found that health professionals can help on both fronts.

Our Drug-Development Pipeline contains 44 investigational and approved agents for MS. Last week, we added two new findings from clinical trials, we updated information from another trial, and we added 10 other pieces of information to the database. The drugs with important additions are alemtuzumab, dalfampridine, fingolimod, glatiramer acetate, idebenone, natalizumab, and teriflunomide. One update summarizes the finding that fingolimod induces the expression of neuroprotective factors by human astrocytes.

[transition music]

And now to our interview with Dr. Gavin Giovannoni, head of neurology at Barts and The London School of Medicine and Dentistry in the U.K. We spoke with him at the recent European Committee for Treatment and Research in MS, or ECTRIMS, meeting in Barcelona about the Brain Health report that was launched at the meeting and about the ORATORIO trial of ocrelizumab in primary progressive MS. We'll cover the Brain Health report in future podcasts with him and other authors of the report. But today, Dr. Giovannoni lays out the methodology of ORATORIO, which may explain some of the very good reduction in disease progression, observed in this trial for the first time in primary progressive MS.

Interviewer – Dan Keller

In the ORATORIO trial, what was the aim, and I guess what's the big outcome?

Interviewee – Gavin Giovannoni

Well, the ORATORIO trial is essentially a phase III trial of depleting anti-CD20 monoclonal antibody called ocrelizumab in primary-progressive MS. As you're aware, almost every trial done in primary-progressive MS has been negative. And then the motivation behind the ocrelizumab trial was based on the rituximab trial; ocrelizumab is a follow-on and rituximab is more humanized, so that should come with fewer side effects like infusion reactions and anti-drug antibodies. In that rituximab trial, there was a subgroup of the population that responded. These were people that are younger and had MRI activity.

So when we designed the ocrelizumab ORATORIO trial, we tried to enrich the study for young people and people that were more active, more enhancing lesions, and we did that. So the population is younger, and the proportion of patients with gadolinium-enhancing lesions at baseline was about a quarter of them. And we also made sure that all the patients had an abnormal CSF spinal fluid. The reason for that is in the Copaxone glatiramer acetate trial, patients who didn't have an abnormal CSF behaved very differently to those with an abnormal CSF, so we wanted to make sure that we had a homogeneous population. And we made sure they had oligoclonal bands or raised IgG in the spinal fluid simply because we we're trying to target a B cell response; so those that are CSF-negative may not be responsive to a B cell therapy.

Lots of features of this trial that we try to wait to make it positive, so we're really, really excited about the results, that people on ocrelizumab had an approximately 25% reduction in confirmed disease progression on EDSS compared to patients on placebo. And it was an event-driven, so the trial wasn't designed to be a fixed time point, it was designed as soon as you got enough events; it was like an adaptive trial, so it was quite cleverly designed in that regard. So it's great news.

Now whether the trial was positive because ocrelizumab is a more effective therapy than the others, or because it's targeting something special like the B cell, at the moment is not known. The only way we're going to find that out is if we do another primary-progressive trial with another highly effective therapy and see what happens there. But this is fantastic news for people with progressive MS. If you follow any patient forums or blogs or whatever, the most frustrated, depressed group is the primary-progressive patients; they've been neglected for years, decades. I think that's the big news, we now will have a therapy which we can offer them.

The one unknown, though, is maybe this result has been driven by a particular subgroup, and I think the regulators and the payers will want to get that data from us. Because if it is driven by a particular subgroup, they may limit the license and the payment for that particular subgroup, the responder group. And so I can't talk to that yet, because most of the subgroup and post-hoc analyses haven't been done. But potentially maybe like the rituximab trial, there will be a proportion of the patients that have characteristic features that are more responsive to the drug, and drive the trial results compared to the other group. And if that is the case, then it's still good news regardless.

MSDF

As it stands now, it seems like the indication would be for people with abnormal CSF, oligoclonal bands, or elevated IgG. Is there any thought that this drug may work possibly by the same mechanism even if you're not seeing abnormal CSF?

Dr. Giovannoni

The spinal fluid tests aren't 100% perfect, so there are people who will have false-negative results. But I've always been a big proponent of the hypothesis that the oligoclonal response in the spinal fluid is something key to this disease. We see that response in infectious diseases like neurosyphilis, measles, rubella panencephalitis, herpes; it's really a signature of its common to infectious diseases, which is why I'm still a supporter of the hypothesis that MS may be an infectious disease. You do find that in a few other autoimmune diseases, particularly the paraneoplastic plastic syndromes, that it's a signature of an intrathecal B cell response. And this drug targets B cells.

One thing it doesn't target, though, it's the long-lived plasma cell, and so CD20 actually stops being expressed, even on plasmablasts, so as soon as you go from the mature B cell to plasmablast to plasma cells, you don't deplete those with anti-CD20. So we know from rituximab data that the oligoclonal bands persist, so we need longer punctures, you don't get rid of those. But until we have long-term followup, we don't know. Maybe drugs that target the plasmablast and the plasma cell will be more effective than rituximab. We don't have any of those drugs available in MS yet.

There's one that's being developed, it's anti-CD19; CD19 gets expressed onto the plasmablast and some plasma cells, and there are some specific markers for plasma cells. But if you gave those to people with MS, you'd probably deplete them of their antibody-producing cells and make them a gamma globulin anemic. Then you'd have to probably then start supplementing with gamma globulin, so it gets quite complicated. But at the moment, the drug will be licensed, I think, for continuous use every 6 months; it won't be induction therapy. Some of the data would suggest you could potentially use it as induction therapy, so, you know, do 2 years and then wait and see if the disease comes back. But the way the drug's been developed at the moment is for continuous maintenance use. There are some concerns; can you continue to use it in the B cell depletion forever? And that's going to have to be answered with the open-label extension studies.

MSDF

Since plasma cells persist and oligoclonal bands persist, if I understood you correctly, do you think that the pathology is mediated through antibody, or this depletion of B cells is acting in a different way, that the B cells are interacting either with T cells or on their own doing something?

Dr. Giovannoni

I mean, there is pretty good evidence from the pathology literature that antibodies are very important in MS. So whether or not you accept it, there is pathological classifications of the top 1 to 4. And there is antibody and complement activation in MS lesions, and there is emerging evidence that so-called grey matter lesions and subpial lesions on the surface are particularly driven by antibody and complement. So I do think they are pathogenic. And so you may get rid of the focal inflammatory lesions that appear to be T cell-driven, whereas the cortical subpial lesions may be antibody-driven. So you may be getting rid of one pathology and not all the pathologies, which is why I remain a little bit skeptical still about whether or not this anti-CD20-depleting antibody will be effective in the long-term. So we may need additional treatment to target plasma cells.

And what you've got to ask yourself really is what's driving those oligoclonal bands. We know they are highly selected, so they're not just there. They're oligoclonal, they've undergone selection by hypermutation, so there's some antigen driving them. They respond to something, and we just haven't been able to find out what they respond to. They are pathogenic, and if we do find the cause of MS, that will almost certainly begins to cause the disease. An analogy would be herpes encephalitis; if somebody's had a herpes infection, then you take those oligoclonal bands out and you absorb them against the antigen from herpes, you remove almost all the antibodies. So they are antigen-specific in the infectious space.

We've tried for years to find out what those bands react against in MS, and we haven't found it. There's several groups still working on it, and I would encourage them to continue working it, because that may be where the action is.

MSDF

The ORATORIO data was only begun to be analyzed very recently. You had mentioned that you were going to be doing subgroup analyses. Are there other analyses yet to come?

Dr. Giovannoni

I mean, the headline results are probably in main secondary outcomes, and there's less of tertiary outcomes. We need to do subgroup analyses trying to look at brain atrophy, the time course of the progressions. I'm very interested in second progressions, because I have this theory that early progressions in progressive disease is not driven by inflammation that occurs in this epoch, it's in the past; so inflammation a year or two ago is driving progression now. And so when you design these progressive trials, a large number of people progress early. And I think it's nothing to do with the trials because it's happened before the trial. So what you then need to do is look at progressions in the future to see if they flatline or stabilize. So there's lots of luck. I think we need to play around with the data, look at the first and second confirmed progressions, incorporate the brain MRI activity as the confounder. There's lots to do, tons to do. But it's good news. The excitement about those analyses are generated because you've got a positive result.

MSDF

Picking up on this idea that what you see today is the result of an insult that happened sometime before, what is the time course that you see using ocrelizumab in terms of benefit; is it so rapid that it questions whether what you said is what's operating?

Dr. Giovannoni

Yes, it's too rapid. When you see the survival curves, they go flat very early, so this is actually saying something else which is really surprising me, which is why I think some of the activity may be driven by an anti-inflammatory, because we know that anti-inflammatory drugs have an effect quite quickly. So that's why I'm suspicious that the positive result is driven by an inflammatory core of patients, and those with the more neurodegenerative or previous inflammation are unlikely to respond. That's my worry with the drug. But let's see what their subgroup analyses show.

MSDF

Anything we've missed or important to add on that?

Dr. Giovannoni

What I want to mention to people with the disease is they shouldn't overhype expectations. The simple reason is when you've got progressive disease you've already lost reserve, so that's why you're progressing. So in early relapsing disease, you make recovery from attacks because you've got ability to recover, a reserve. And so early on you stabilize or improve, and later on you slow down progression. So I'm trying to tell people with the disease if you do go into this therapy, don't expect to improve or get better. You're much more likely to progress more slowly, which you won't notice. It's hard in an individual to say they're progressing more slowly, or you'll plateau out and stabilize. I think that must be the expectation, rather than improvement. And I think we need to manage those expectations, that people may not at a personal level find a big dramatic response in terms of their disability on the drug.

MSDF

But this sounds like – getting back to the discussion of the Brain Health report – where you should diagnosis and treat rather quickly. At least now if someone comes in with primary-progressive, there may be at some point something to do from the start.

Dr. Giovannoni

Yeah. Well, it's like with any neurodegenerative disease, the sooner you treat the more you've got to protect, and the later you treat the less you've got to protect. So this would be a call to get primary-progressive disease diagnosed as soon as possible and treat as soon as possible. And if you look at the diagnostic delay in primary-progressive disease, it's probably worse than relapsing disease. People often go years before being diagnosed. So we're going to have to sharpen up the referral pathways and the diagnostic pathways in primary-progressive disease to get that timeless brain concept across there, too.

[transition music]

Thank you for listening to Episode Fifty-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 Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. 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.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[outro music]

[intro music]

Host – Dan Keller

Hello, and welcome to Episode Fifty-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. Michael Levy, who discusses the status of regenerative stem cell therapies for multiple sclerosis. But first, here are some new items in the MS Discovery Forum.

Our lead story last week looked at a way to prevent a rare but dangerous viral brain infection that can be a side effect of certain drugs. The risk of infection limits the people who can take natalizumab to prevent the inflammatory brain attacks of relapsing-remitting MS. Two new papers propose vaccinating people against the virus. Experts are still debating the underlying biology, but they say the approach should be tested in people.

Every week, MSDF lists the latest scientific papers related to MS, with links to the abstracts on PubMed. Of more than 100 new studies published last week, we selected three as editor’s picks.

One study comes from the Italian registry of pediatric MS patients treated with natalizumab. Researchers evaluated 101 boys and girls. Natalizumab was safe, well tolerated, and effective, they report. Time on the drug varied, but the overall mean was about three years. Most of the patients switched because of a poor response to first-line drugs, such as interferon-beta and glatiramer acetate. The patients’ sera were assessed for anti-JC virus antibodies to prevent the rare but dangerous brain infection associated with natalizumab.

Two other studies caught our eye this week. One goes into the new insights from live imaging in the central nervous systems of mice. The authors outline potential applications that could lead to therapies to protect or restore myelin. Another study asked if spasticity of lower limbs could be helped with anodal transcranial direct current stimulation in 20 MS patients. The answer is no, based on the results of the small randomized double-blind clinical trial. This is not to be confused with another noninvasive technique that seems to reduce spasticity, called transcranial magnetic stimulation.

Our Drug-Development Pipeline contains 44 investigational and approved agents for MS. Last week, we added an extensive meta-analysis of clinical trials, we updated information on three trials, and we added 16 other pieces of information. The drugs with important additions are alemtuzumab, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, GNbAC1, interferon beta-1a, interferon beta-1b, laquinimod, mitoxantrone, natalizumab, ocrelizumab, and teriflunomide.

One update reflects the finding that ocrelizumab slows disease progression in primary progressive MS, the first drug to do so, as described in the drug-maker’s news release. Another update reflects a meta-analysis by the Cochrane Multiple Sclerosis group. It compares 39 different clinical trials involving more than 25,000 patients to rank benefits and acceptability of 15 different MS drugs. Doctors and patients need even better information to make decisions, the authors conclude. They call for more randomized studies directly comparing active agents, no more placebo-controlled studies, and long-term followup of all drug studies.

The MSDF team is attending this week’s ECTRIMS meeting in Barcelona, Spain. If you, too, will be at the conference and would like to meet with us – or if you’re interested in being interviewed about your research for a future podcast – please email us at editor@msdiscovery.org.

[transition music]

And now to our interview with Dr. Michael Levy, assistant professor of neurology at Johns Hopkins University. We met in his office to talk about stem cell regenerative therapies – what the aims are and where things stand.

Interviewer – Dan Keller

Let's talk about regenerative stem cell therapies, but I suppose the first thing to make clear is nothing is approved yet, is that right?

Interviewee – Michael Levy

Nothing is even closed to being approved. There are many trials in progress in multiple sclerosis and in spinal cord injury, which is a related demyelinating condition in which stem cells are being tested, and this is worldwide, probably over 20 studies that are ongoing.

MSDF

What are some of the goals?

Dr. Levy

The goals are twofold. In multiple sclerosis in particular, the two goals are to recover function and to neuroprotect against future insults. So in spinal cord injury, for example, there's only one goal which is recovery of function, because they don't have to worry about future insults.

MSDF

Now no one really has the exact idea, or I guess there's many ideas, of how these would work – whether the cells would actually replace lost cells, whether there's secreted trophic factors – so are people looking at them specifically in those areas, or whatever works at this time, then they'll figure out why?

Dr. Levy

It certainly started off with the mechanism in mind that the cells would replace lost tissue. That was really how things started. But as they've evolved, patients have responded in part to many different types of stem cell therapies, and none of them have involved replacing lost tissue. And so there are probably many different mechanisms involved, and it's evolved into exactly what you've described, a phenomenon of wow, this really works, let's continue it and let's try to figure out what's going on in parallel.

MSDF

Is there also a thought that the stem cells really are just providing a supportive environment, or even a supportive structure, for natural processes to proceed if they have the right setting?

Dr. Levy

Oh, sure. There are some studies where the stem cells only survive, or are only around, detectable, for about one hour, and then beyond that they can't be detected, but yet they provide some significant long-lasting benefits. So exactly how they do that is not clear.

MSDF

Are you familiar with the mouse experiments of Jeanne Loring at Scripps; she had taken human pluripotent stem cells in a mouse model and they were gone after a week, but then the mice got up and walked around and seemed to look perfectly normal.

Dr. Levy

So definitely mouse models have recapitulated what we've seen in humans, which is that the stem cells provide some sort of benefit. Whether it's secretion of trophic factors, or neuroprotection or replacement of tissue, or what they call neural bridging, allowing neurons to communicate through in the alternative circuit, this is true in mice, too. So whatever is happening in humans is probably also going on in these mice.

MSDF

Specifically in the MS area, what are people or companies doing?

Dr. Levy

Specifically in MS, the most common trial that's being conducted now is testing mesenchymal stem cells--taking them from that patient, usually from the hip, purifying them in the lab, and then injecting them back into the patient, either into the bloodstream or into the spinal fluid. Initially, the goal was to try to replace lost tissue, but now the goal has evolved, and what these studies are really looking for is sort of the 6-month or 12-month outcome to see if patients recover better, have fewer relapses, and better outcomes.

MSDF

Now mesenchymal stem cells in themselves are not going to turn into the lost kinds of cells you really want to replace, but they do have immunomodulatory effects, is that right?

Dr. Levy

That's the thought. So mesenchymal stem cells are all the cells in the bone marrow that don't turn into blood cells, either red or white blood cells; it's the rest of the matrix. And in the lab, you can turn them into neuronal cells and supportive cells that you find in the brain, but that doesn't happen when you put them into spinal cord or brain; they don't tend to differentiate into neural tissue. And so they are doing something else, and part of that is probably neuromodulatory. Correct.

MSDF

Besides mesenchymal stem cells, people are looking at a little more differentiated cells, oligodendroglial precursor cells--you obviously want to remyelinate. Do you have an idea of what's going on with those and has there been success there?

Dr. Levy

So all the studies using neural stem cells and neuroglial stem cells are currently being conducted in spinal cord injury. And in spinal cord injury there is a component of demyelination, and they're hoping that those oligos migrate to that area that is demyelinated and that it will remyelinate the lesion. So all MS patients should keep an eye on those studies to see how those turn out.

MSDF

The difference there is you can identify an area of lesion. In the brain, you don't know exactly where lesions are going to come up, and lesions disappear also.

Dr. Levy

MS patients tend to have dozens of lesions, and many could be in the same pathway. So even if you remyelinate one, there could be one upstream or downstream of that lesion that's still impairing the function. In spinal cord injury, there is just one lesion, and they're trying to remyelinate just that one; you're correct about that.

MSDF

Are you familiar with the work by Basil Sharrack in England? There were about 10 patients, I think. They did myeloablative therapy and autologous bone marrow transplants, essentially as they called it, rebooting the immune system. That's obviously a stem cell therapy in a sense.

Dr. Levy

Absolutely, it is a stem cell therapy. The thought there is – exactly like you said – rebooting the immune system; taking out only the most immature stem cells that haven't been exposed to whatever the trigger of their disease was, taking those stem cells out and sparing them, holding them in the lab, then getting rid of the rest of the immune system in the patient's body and reintroducing those stem cells back; as you said, rebooting the immune system to see if we could return their immune system back to the pre-MS state and see if that has a better outcome. And, generally, those types of studies where we're really ablating the immune system have tended to have good outcomes; some patients are able to come off of therapy for years, but ultimately the disease comes back. And it could be years; it could be five, even up to ten years. And so we really have to understand why that is. If there's another environmental exposure or if there is just something really genetically encoded into the immune cells.

MSDF

Or, for example, if there's an EBV etiology, the Epstein-Barr virus is still there probably

Dr. Levy

That's right, so EBV may be that environmental trigger.

MSDF

One thing I don't understand about that is they reported, I think, in Science Translational Medicine, that people who had pretty significant disability – you know, using a wheelchair – could then walk again. It seems rebooting the immune system should not do anything to reverse or restore neural function.

Dr. Levy
That would be my expectation, too. So in any study where we're looking at effects on the immune system, I wouldn't expect the nervous system to have such a dramatic recovery either. That was a surprise.

MSDF

What else is there to say about stem cell therapy's messages to physicians who are asked about it, messages to patients who are interested in it at this point?

Dr. Levy

At this point, I would say that the verdict is still out, that the studies need to be completed, and that there are a lot of companies out there offering "stem cell therapies" to patients with MS, who are just looking for anything to improve their function. And that can be dangerous, because we don't really understand this science works, and there have been some bad outcomes reported in the literature from patients who are seeking this type of care from clinics offering "stem cell therapies." And I would just caution patients and caution doctors to wait until these studies are done and we have a better sense of how they work.

MSDF

There seems to be a lot of fly-by-night operations on the internet and overseas, and things like that, but even with legitimate trials I would guess there could be bad outcomes. What sorts of dangers are there in stem cell therapy?

Dr. Levy

There are two. One is that the stem cells will develop into tumors, because these stem cells are now able to proliferate, that's one of their features. So a concern is that they're going to proliferate uncontrollably into a tumor. And the second concern is that you're reintroducing a foreign cell – in some of the trials they're foreign cells – and that might trigger a relapse. So if you inject it directly into the spinal cord, could you then cause another inflammatory event in the spinal cord targeting those stem cells? So those are the two major concerns.

MSDF

Is there anything important to add, or that we've missed?

Dr. Levy

No, I would say that pretty much covers it.

MSDF

Well, thank you.

[transition music]

Thank you for listening to Episode 55 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 Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. 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.

For Multiple Sclerosis Discovery, I'm Dan Keller.

[outro music]

Transcript will be available Friday, Oct  2

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Host – Dan Keller
Hello, and welcome to Episode Fifty-Three of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features Dr. Jonathan Kipnis, who discusses his recent discovery of lymphatic vessels in the meninges. But first, here are some new items in the MS Discovery Forum.

According to our curated list of the latest scientific articles related to MS, 34 such articles were published between August 21st and 28th. To see these publications and the articles we selected as Editors Picks, go to msdiscovery.org and click on Papers.

Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. This week, we’ve added 6 pieces of information about alemtuzumab and fingolimod. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.

The MSDF team is looking forward to attending next month’s ECTRIMS meeting in Barcelona, Spain. If you, too, will be at the conference and would like to meet with us – or if you’re interested in being interviewed about your research for a future podcast – please email us at editor@msdiscovery.org.

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And now to Part 1 of our interview with Dr. Jonathan Kipnis, Professor of Neuroscience and Director of the Center for Brain Immunology and Glia at the University of Virginia in Charlottesville. His group recently published in Nature their discovery and characterization of lymphatic vessels in the meninges.

Interviewer – Dan Keller
You've described in this paper about meningeal lymphatics, the novel but actually more conventional path for cerebrospinal fluid drainage from the CNS than I guess had been thought of before; it's sort of conventional as revolutionary. Can you tell me what you found and what led you to look?

Interviewee – Jonathan Kipnis
Yes, so we've been interested in the role of meningeal immune system for quite some time, and we've shown that changes in meningeal immunity could impact brain after a CNS injury, or also for normal brain function. So, for example, mice that have impaired meningeal immunity would show cognitive deficits and would show some little bit more prone to stress and other phenotypes.

So we've been very interested in understanding how meningeal immunity is being regulated. So the assumption was at some point that there is no immune cells in the brain, which is true, except for microglial which reside in the brain and compose 10% of the brain cells, but there is no peripheral immune cells within the brain. But in very nearby areas, which is the surroundings of the brain – the choroid plexus, the meninges, and the CSF – that's where actually there are immune cells, and there are all types of immune cells. And so we have been very interested to understand how the cells are getting in and getting out.

Through the use of parabiotic mice, we demonstrated last year, we showed that immune population of the meninges is not static; the cells are being repopulated, and about 50% of T cells, for example, is being exchanged within about 10 days, and major exchange between the CSF or the meninges with the deep cervical lymph nodes. So nothing was really new, we just sort of established things maybe more solid way. Those cells can get in while still nobody understands very well how they get in; we'll assume they get in through the meningeal vasculature, which is probably true.

But then how do they get out, or what happens with cells after they get to the CNS? Well, the assumptions were, well, they either die, magically disappear, or crawl under the nose through the cribriform plate and into the deep cervical lymph nodes through the nasal mucosa. They were okay explanations, but in our systems we did not find any of it to be sufficiently explaining what's going on in this really fast and pretty dramatic exchange of the immune system within the meningeal spaces.

So when we just looking at it a bit closer, and it is very, very well established that there is lymphatic drainage from the CNS, so this needs to be remembered. So people in many labs have shown that if you put stuff in the brain – which stuff I mean proteins – if you put proteins or antigens in the brain, whether it's in the parenchyma or in the meninges or in the CSF, you will find those proteins, and you will find immune response to these proteins in the deep cervical lymph nodes.

The question is, of course, how do they get there? And the path which was described just did not work in our hands, and so I was lucky to get a very, very talented postdoc, Antoine Louveau, at the lab. He realized that for us to understand how things get in and out, the only way to do it is to do live imaging and also to do a whole mount of the entire meninges. And I think that's when it was a breakthrough point. So Antoine laid out the entire meninges and was looking for location of the immune cells. And he said let's see where I see maximum accumulation of the immune cells, and then let's see how these places will change when we expose mouse to, for example, stress, learning, or EAE inflammation, viral infection, or whatever, let's see how these areas of dense immune population will change.

And so he realized that there is a lot of immune activity around the major sinuses in the meninges, and then he saw that there are immune cells which are in the vascular structures which were not blood vessels. And I think that was the turning point. And I said, okay, if the cells are within the vasculature which is not blood vasculature, what would it be? Well, so I went to colleagues here and said what do you label lymphatic vessels with? And they didn't understand why would you want to label for lymphatic vessels, because they don't work with the brain. And so we labeled a lymphatic marker and we saw the vessels, which were lining the major sinuses and going all the way along them. So that's a very long answer to your very simple question.

MSDF
And Antoine Louveau's technique here that was the key to it was doing in situ fixation so he could get the meninges out intact?

Dr. Kipnis
To let's assume the meninges came out intact on the brain, and let's assume we had this beautiful staining. Let's say we did the coronal staining, and let's say we're labeling for lymphatic vessels. So you can imagine that what you'll see is at the border of the brain you will see a dot; you will see maybe three dots because there are three vessels going along the sinuses. And when you see a dot, you never take a dot seriously in immunohistochemistry. Now that we know that this dot represents the vessel, then we can actually go back and do those coronal sections and look at it. But back then only by seeing the whole meninges mounted as one on a slide, and by seeing those vessels there, I mean that's when we knew. And so to us it was obvious this is something that absolutely went under-noticed. And this technique of whole-mount meninges, I think, was absolutely crucial.

MSDF
Did he find these vessels in all layers of the meninges, or any specific ones?

Dr. Kipnis
No, no. Major lymphatic vessels are following the superior sagittal and the transverse sinuses, which is in the dura. So all the blood from the brain is being – at least in mice. In humans it goes a little bit different, but also through the sinuses, although sinuses are located so not all the blood in the human brain goes through the parasagittal sinus, but in the mouse brain all the blood goes through the sinuses in the dura. So major sinuses through which all the blood is being collected from the brain, and then goes out there. And so along those sinuses we find the lymphatic vessels, so they are sitting in the dura.

MSDF
And this system also has been found in humans?

Dr. Kipnis
Well, that's a good question. You know, it's very hard to obtain high-quality human samples from the dura, because nobody really cares about this area. So we were lucky in the triple operation of Bea Lopes, who's a really great neuropathologist here at UV; she was able to give us, I think, nine samples from patients of dura of the sinus; these were all fixed in formalin. So we looked at those, and as you can imagine, the sinus in the human is huge, so obviously compared to a mouse. So in two out of nine, we were able to identify vessels that looked like meningeal vessels, but I think it warrants much deeper and much farther investigation to be able to say, yes, here they are. But if you ask me personally, why wouldn't they be? Why would mice have them and humans won't have them. So I think it's a matter of identifying their location and the best markers to use for them, but I think they should be there again. In two out of the nine samples, we were able to demonstrate that this is something that looks very, very good.

MSDF
And you did immunohistochemistry on these to show the lymphatic properties and not general blood circulatory vasculature properties, either in the mice or human?

Dr. Kipnis
Oh, yes. So in the mice we identified the characteristics of those vessels really, really well. You know, nothing is perfect, that every marker on mouse markers are expressed by different cells, so you need here to provide a series of markers and to demonstrate that this is also indeed the real lymphatic cells. So we stained for LYVE1 and we showed beautiful staining with LYVE1, also with macrophages. And those are vascular structures and they came out to be macrophages. But one of the major transcription factors that will define lymphatic and endothelial cells is a Prox1. So we demonstrated two ways of Prox1; one is transgenic mouse and the other is staining for Prox1. And we also did two other molecules. One is a Podoplanin which is expressed in tissue lymphatics, and these vessels are expressive.

And the other molecule, she is very interesting. It's a receptor for VEGF3, VEGF-C. And this receptor is first on the lymphatic and endothelial cells. In the periphery, lymphatic and endothelial cells will respond to recombinant VEGF-C and will expand. So what we did here, we also injected a recombinant VEGF-C and we showed these vessels expanding. So we know now that the receptor is actually functional in the vessels, but also we now can expand the vessels. Whether it will impact any neurological disease, we don't know, but at least we have the capability to do so.

And then we also identified them by flow cytometry. We took samples from skin and from diaphragm where lymphatics are very, very well defined, and using the exact same antibodies we did also flow cytometry on our meningeal samples. And we show that the cells look exactly like they look from the skin and from the diaphragm; of course, the numbers are much smaller. So I think in terms of their calculation in a mouse, we are very convinced.

Now for humans it's more difficult. Like I said, the sample was in formalin and it's very hard to work with those samples, and, again, the area is huge to go through. So we were able in humans to get two markers to work; one was LYVE1 and the other was Podoplanin. We could not make Prox1 to work, I think it's a problem with the antibody and not with the vessel or potentially with the tissue as well. And these vessels would not label for some other markers, which would be characteristic of, for example, macrophages. So we were able to attack on them two out of four markers that would potentially allow for him to see. But we are now trying to identify those vessels by other means in humans as well, and I think flow cytometry may be the way to go.

MSDF
Now you've shown that these lymphatic vessels drain into the deep cervical lymph nodes, and it looks like you've also been able to rule out drainage through the cribriform plate back into the cervical lymph nodes. Is that true?

Dr. Kipnis
I'm glad you bring this up, this is very important. So if you think of CSF, CSF is composed of several things. So we have the liquid itself, we have the macromolecules within the CSF, and then we have the immune cells within the CSF. So I don't think there is anybody would argue against liquid being drained through the cribriform plate and through the granulation; this is funny to argue. And obviously we are not claiming anything until we're absolutely sure; there is beautiful works from many, many labs showing that. But for the macromolecules and for the immune cells, the path which was proposed through the cribriform plate most probably if it's not a wrong one, it's probably not the major one.

[transition music]

Thank you for listening to Episode Fifty-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. 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 Fifty-Two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features Dr. David Tabby, who discusses the incidence of headache in MS. But first, here are some new items in the MS Discovery Forum.

According to our curated list of the latest scientific articles related to MS, 53 such articles were published between August 14 and 21. To see these publications and the articles we selected as Editors Picks, go to msdiscovery.org and click on Papers.

We’ve made some recent updates to our Funding Opportunities and our Meetings and Events listings, both of which can be found under our Professional Resources tab. Be sure to take a look at a newly-posted funding announcement entitled, “National MS Society: Health Care Delivery and Policy Research Contracts.” If you know of any meetings, events, or funding opportunities that are missing from our lists, please email us at editor@msdiscovery.org so that we can include them.

Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. This past week, we’ve added one new trial and 15 other pieces of information. The drugs with important additions are dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, and ofatumumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.
 
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And now to the interview. Dr. David Tabby is an adult general practice neurologist, with a subspecialty in multiple sclerosis, in Bala Cynwyd, Pennsylvania. He was formerly associated with Drexel University College of Medicine in Philadelphia where he carried out the study on headache and MS that we discussed.

Interviewer – Dan Keller
Could you just tell me what the aim was? I think you were looking the variables affecting headache occurrence in MS patients.

Interviewee – David Tabby
Well, to be perfectly frank about that, my business manager had noted that many of my MS patients also had migraine, and she asked what’s going on with that. So we did a cursory review and found that close to 50% of my MS patients also had migraine. So that prompted the survey in a more formal fashion.

MSDF
Whom did you look at, and what were some of the variables you looked at?

Dr. Tabby
Well, we looked at everyone who was willing to answer a survey. And we wanted to include some typical migraine variables like frequency and intensity and triggers and age of onset and duration at that time and which came first, MS or migraine.

MSDF
And what were some of the major findings?

Dr. Tabby
I think our biggest contribution was that it seemed that we could correlate exacerbations with increase in headache, which I don’t think was known before that. Sometimes headache a little bit before the exacerbation, and sometimes exacerbation first, then with headache. But that raised the question about the role of inflammation in both headache and MS exacerbations. You know, I don’t think one is the cause of the other, but they’re clearly related.

MSDF
What about migraine with aura or without? Are there differences in the MS presentations or symptoms or relations in time?

Dr. Tabby
We didn’t have a lot of migraine with aura patients. That’s only about 20% of the migraine population anyway. We didn’t have a big enough number to make any kind of association that would be distinguishing migraine with or the migraine without aura.

MSDF
Do you have a proposed mechanism in mind how these two may be linked – mechanism of migraine, mechanism of MS?

Dr. Tabby
I don’t think there’s a lot of work about what the immune system’s role is in migraine, but stress affects the immune system. My patients tell me that a particularly stressful event can seem to precipitate an exacerbation, and, no big secret, that stress can precipitate a migraine.

MSDF
Fatigue can be a trigger, and obviously, that’s a large proportion of MS patients have it. So do you think there may be a link there, one triggering the other?

Dr. Tabby
90% of MS patients will complain of fatigue at some point, and I think that’s clearly got something to do with it. So anyone with migraine will tell you that when they overdo it and get overtired, they get a migraine.

Interviewer – Dan Keller
I think I saw something in the paper was talking about metalloproteinases in the CNS and leakiness of vessels and allowing either antigens out or T cells in. Does that have any legs or where does that idea come from?

Dr. Tabby
That idea came from a paper that we found in our literature review of the basic pathophysiology of an MS exacerbation that matrix metalloproteinases have to be activated first, to increase vascular permeability of the CNS. Migraine was thought, at one time, to be a primarily vascular issue. It’s not. It’s primarily a neurochemical issue that affects the vasculature, but results in dramatic changes in blood vessel permeability. There’s a kind of leakage of fluid around blood vessels, which helps make them more sensitive.

MSDF
There’s also a component of calcium flux in migraine. Would that have any effect on the immune system? There’s calcineurin inhibitors that are immunosuppressants, so I’m wondering if calcium in itself – could be an imbalance be a stimulant?

Dr. Tabby
The role of calcium in modulating neural function can’t be overstated. I’m not ready to give you an exact mechanism of how that might function.

MSDF
Patients with migraine supposedly have more symptomatic clinical course of MS. Do you have any numbers there? What did you find?

Dr. Tabby
We weren’t a longitudinal study. We’re really just a snapshot kind of picture to determine, you know, a relationship now. That was another one of our hypotheses that the worse headache you had the worse MS you were going to have. Our take-home message from the paper was MS doctors should be very aggressive about addressing migraine symptoms in their patients, because we think that it could have an effect in long-term prognosis in MS. And it’s not just the patient complaining about, oh, I have a really bad headache. There is a relationship. It’s been known for many years. I mean, you might have seen in our bibliography that some of the papers went back to the 1960s about the relationship with headache and MS. So, just to reiterate, migraine prophylactic therapy, migraine abortive therapy is important in the context of treating MS.

MSDF
Can pre-existing migraine before the MS diagnosis give you any clue as to being a risk factor in itself?

Dr. Tabby
That’s an excellent point. We didn’t have a big enough group to come to that conclusion, but 12% of Americans have migraine – 18% of women, 6% of men. Less than 1% of the population has MS. Something else has to be happening.

MSDF
Also, I guess you found that people with stabbing pain had more acute MS exacerbations than if they had other more throbbing kinds of pain.

Dr. Tabby
Well, we were just using that as an indicator of severity of the headache. Stabbing’s not a typical word used to describe migraine. We gave choices. We just didn’t leave it open-ended. We gave some example words for their responses to the survey to tick off. Yes, stabbing was one of them, and there was a correlation between the ones who said stabbing and worse exacerbation.

MSDF
Some of the patients you surveyed did not have pre-existing migraine, only after their MS diagnosis. Do you think that migraine is something that one should investigate whether they actually may be in a prodrome of MS, if they present late - develop migraine late in life – later in life?

Dr. Tabby
In our world, pretty much everyone with a bad headache who sees a doctor about it, at some point is going to get some sort of imaging study of the brain. It might be a CAT scan, in which case there might not be enough information. But if it’s an MRI, there’s a good chance of seeing high-signal lesions scattered through the white matter. They may be real small and not particularly typical of MS. But not uncommonly, they’ll see a pattern that looks really quite like MS. And you examine the patient, and you don’t find anything that’s consistent with MS. You do a history, and you don’t find any symptoms that are consistent with MS. So this is the sort of thing you just file away and see what happens. I don’t think anyone would suggest that treatment for MS should be started at that point.

There’s an entity that’s finally gotten a name, called radiologically isolated syndrome, which people get MRIs of their brain for some reason – head trauma, headache, anything really – and the pattern looks really quite like MS, but there’s no clinical support of MS. So same thing; we don’t forget about these people. You recheck their MRIs at some point in the future. You look for new lesions or enhancing lesions. I think the latest statistic is somewhere around 50% of them are eventually going to present as having multiple sclerosis.

MSDF
Would each entity be treated or each condition be treated as if it existed in isolation? Or do they complicate the management of the other?

Dr. Tabby
My approach has been to treat them independently. Just follow the basic principles of headache treatment for the headache and the basic principles for MS treatment and adjustments of therapy and symptomatic therapy for MS. I would not suggest some interlinked therapy system.

MSDF
But something like interferon and possibly other drugs may cause exacerbation of headache. Would that lead to noncompliance of the MS treatment or would you switch drugs or how do you handle that?

Dr. Tabby
That doesn’t necessarily involve the headache issue. I think someone who has bad headaches on interferon who’s not taking their medicine, you know, you might try to fix it – fix the headache that is. But you’re probably fighting an uphill battle when that patient has negative associations with taking their medicine. I still tend to think of these two things as related but separate.

MSDF
So what’s the big take-home message for a physician?

Dr. Tabby
Really just about treating migraine aggressively in their MS patients, and keeping in mind that we work very hard to preserve function to reduce the accumulation of disability, with drugs and other sorts of interventions. But intervening for migraine may be just one other way to reduce the burden of disability in the future, for your patients.

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MSDF
Thank you for listening to Episode Fifty-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. 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 Fifty-One of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.

This week’s podcast features Dr. Luke Lairson of Scripps Research Institute, who discusses discovery of small molecules to induce remyelination and, in particular, some muscarinic receptor antagonists currently approved for other indications. But first, here are some new items in the MS Discovery Forum.

According to our curated list of the latest scientific articles related to MS, 114 such articles were published in the first two weeks of August. We selected a few of these articles as our Editor’s Picks. One is a longitudinal study of gray matter lesions and cortical atrophy in MS published in PLOS ONE. The investigators obtained MRIs at baseline and five years later from subjects with clinically isolated syndrome, early and late relapsing-remitting MS, and secondary progressive MS, and examined lesion placement and cortical thinning in the different disease subtypes. To see this publication and the other articles we selected, go to msdiscovery.org and click on Papers.

Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week, we added 1 new trial, we updated information on 2 other trials, and we added 12 other pieces of information. The drugs with important additions and changes are ATX-MS-1467, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, and interferon beta-1b. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.

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And now to the interview. Dr. Luke Lairson is an assistant professor at the Scripps Research Institute and a principal investigator at Calibr, the California Institute for Biomedical Research, in La Jolla. We spoke at the research institute.

Interviewer – Dan Keller

Dr. Lairson, we're talking about the potential for remyelination. And your institution is taking a very systematic and maybe novel approach. Can you describe how you're going about looking at possible ways to induce remyelination?

Interviewee – Luke Lairson

Sure. So we're using a phenotypic assays to look for small molecules that selectively induce the differentiation of the precursor cell population which is required for remyelination, which are the so called oligodendrocyte precursor cells or OPCs. We developed imaging-based assays where we could look for small molecules that selectively induce that differentiation phenotype.

MSDF

And how are you going about screening compounds, and what is your institute set up to do?

Dr. Lairson

So at Scripps and Calibr we have the capacity to screen on a million compound scale capacity to look at molecules. In this particular assay, we do it in a 3D four-well format, which limits us to screening collections on the scale of hundreds of thousands. And to date, we've screened about 200,000 compounds with this assay.

MSDF

In terms of multiple sclerosis, what are you looking at now?

Dr. Lairson

From our preliminary screen of our collection of bioactive compounds, including FDA-approved drugs and drugs in late-stage clinical development, we identified a series of compounds for which OPC differentiation had not been previously reported, which are muscarinic receptor antagonists, which are clinically approved drugs and which work in the central nervous system. And we demonstrated a number of these compounds work in two different rodent models of remyelination in MS. And we're currently developing these as a lead class of compounds as a combination therapy when combined with existing immunosuppressant drugs, including Gilenya.

MSDF

What compounds have you focused on most? There's a multitude of approved antimuscarinic agents.

Dr. Lairson

Right. So this is actually a a critical point. So we identified a number of compounds which had antimuscarinic activity, which were active in our OPC differentiation assay. We used pharmacology to demonstrate that the antagonism of M1 or M3 receptor subtype is a required component of the mechanism of these drugs. However, we think that there's a second target, and it's a dual mechanism action through which these drugs are acting, which we're currently trying to elucidate what that second target is to fully characterize the mechanism. That second target actually provides the opportunity to identify compounds that have a potential to have a better therapeutic index in vivo. So the lead compound we published was benztropine. Jonah Chan's lab at UCSF later showed that clemastine also works, which was in our paper, as well. So these are drugs that have been demonstrated to work in vivo.

What we did after we published that is we then looked at every compound that we could get our hands on that had antimuscarinic activity – specifically targeting M1/M3 receptor subtypes – and then characterized their activity in the OPC differentiation assay and, as well as profiling their potency on the M1/M3 receptor subtypes, with the goal of looking for compounds that have an optimal therapeutic index in terms of on-target toxicity. So benztropine induces OPC differentiation in the low micromolar range, but it antagonizes M1 and M3 receptors in the low nanomolar range so there's a discrepancy there. And we think that the on-target toxicity of antimuscarinic activity is going to limit the therapeutic potential of these drugs. We've since identified other FDA-approved drugs for which that index is improved and we compounds with approximately 100-fold improvement in therapeutic index, which we've demonstrated in the EAE model are active. And we're currently evaluating them in combination with immunosuppressant drugs to identify an optimal combination, which could well be benztropine or clemastine but may be another FDA-approved drug.

MSDF

You're at very early stage in terms of clinical utility of these things in MS. But is there any way to separate out the negative antimuscarinic effects that affect people taking drugs for overactive bladder and various other things from their therapeutic effect? Or is it really intrinsic to attacking that receptor?

Dr. Lairson

That's the key point. So we do think that it's that on-target toxicity which is going to potentially limit this class of compound, which is why we're looking for these other compounds and where we have an improved therapeutic index of inducing remyelination versus antagonizing those receptor subtypes. And likely this class of drugs – and any class of drugs that induces remyelination – is going to have to be used in combination with immunosuppressant drugs. It will require a careful clinical evaluation to figure out which combination will be the most effective and what doses will be safe.

MSDF

But you also have been doing T-cell assays I take it in looking at benztropine in your work. So what goes on with immune modulation? Is there any effect there?

Dr. Lairson

So we did extensive studies with benztropine to evaluate its activity in not just T-cell biology but also macrophage biology both in vitro and in vivo. And we found benztropine had no affect on in vitro or in vivo T cell numbers or activity in terms of cytokine production. It has no affect on macrophage polarization in vitro or in vivo, including looking at spinal cords of animals. We don't think that it's acting through a peripheral immune system effect. We can't rule out an important concept that came out at a recent meeting was we need to look at the affect of these compounds on microglial cell activation in the brain and also in astrocyte activation.

MSDF

So it looks like it's a pure remyelination effect at this point and not really an immunosuppressive effect, which would argue for having to use it in conjunction with today's drugs for MS.

Dr. Lairson

Correct, that's our current reasoning, yeah.

MSDF

Have you looked at other models other than cuprizone?

Dr. Lairson

Yeah, we looked at the EAE…PLP-induced EAE model of relapsing-remitting MS, and we've looked at the MOG model of progressive MS and the cuprizone model. Yeah, those are the models we've looked at to date.

MSDF

With similar results?

Dr. Lairson

The compounds we've evaluated have all been active in in those models.

MSDF

Do you have an idea of the mechanism of action how this is actually working in the oligodendrocyte precursor cells?

Dr. Lairson

Downstream of the muscarinic receptor…so as I said, based on pharmacology, these classes of compounds – these neurotransmitter receptor modulating agents – are notoriously pleiotropic in that they had multiple receptor subtypes in the brain. So benztropine, for example, it hits nicotine and histamine receptors in this dopamine reuptake inhibitor in addition to being an antimuscarinic. We've shown that those activities are not responsible for inducing OPC differentiation. However, as I said, we've identified multiple compounds that do inhibit muscarinic receptors – specifically receptor subtypes 1 and 3 – that do not induce OPC differentiation. So we think there's a second target; we're actively trying to identify what that second target and downstream mechanism is.

MSDF

Do you think the same compound would attack both targets, or are you going to need to give multiple compounds to hit multiple targets very selectively as I would think would be the hope?

Dr. Lairson

The existing compounds we have the argument is that they are hitting both of these targets to induce the differentiation. In that, there's a number of compounds that do hit the M1/M3 receptors that do not induce differentiation, which argue that you need both. The compounds we've identified fortuitously hit both of the necessary targets.

MSDF

In the antimuscarinic field, often the goal is to be very selective and limit activity at different receptors, but it sounds like you want some overlap here.

Dr. Lairson

Exactly. We've also initiated some medicinal chemistry where we're trying to see if we can dial in potency for the second target. So we know if benztropine is active on muscarinic and low nanomolar can we improve its potency in the OPC assay by dialing in potency on that second target?

MSDF

By modifying the molecule?

Dr. Lairson

Yeah, so making analogs of existing active antimuscarinic agents and then evaluating their activity in the OPC differentiation assay, as well as evaluate their antimuscarinic activity.

MSDF

Are you hoping that the same active part of the molecule hits both receptors, or have you ever considered making a bifunctional molecule that would be best at both receptors?

Dr. Lairson

If we knew what the other receptor was, we could potentially address that, or you could argue a bifunctional versus having two unique compounds so it would be you'd have to evaluate that in vivo I think, yeah. The other argument for moving away from this is that as soon as you make a change to that compound it's no longer an approved drug, and you have to go through the rigor of bringing that to the clinic.

MSDF

Now in your screening, you're using a lot of drugs – a lot of compounds at this point – that have already passed phase 1 screening or phase 1 clinical testing, and this has shown safety. Does that speed up do you think the approval process if these things look active?

Dr. Lairson

It does. So UCSF has actually initiated a phase 2 trial to evaluate clemastine in MS. So they were able to immediately proceed from a screening result to a clinical trial because it's an approved drug.

MSDF

And just about Calibr, your institute. You have full facilities for taking this from screening up to what stage?

Dr. Lairson

Up to the rodent proof of concept stage. So we have a high throughput screening facility, as I mentioned, and then we have a medicinal chemistry group, a pharmacology group where we can do pharmacokinetics in-house and then in core biology. So we take it to the rodent proof of concept.

MSDF

Do you do any synthetic chemistry, or this is all screening of existing molecules?

Dr. Lairson

Yeah, we do significant amount of synthetic chemistry so we have a group of 20 chemists – medicinal chemists – that are making analogs. And we do a significant amount of contract research to get compounds and analogs made.

MSDF

What have we missed, or what do you think is important to add, if anything?

Dr. Lairson

The other aspect of our program is we've identified novel compounds for which their mechanism of action is unclear. So we've identified multiple scaffolds. We've focused on three of those, which have been subjected to medicinal chemistry optimization. So we identified screening hits, which we were unable to evaluate in the rodent models due to their pharmacokinetic property. But we've now identified analogs of those compounds which are potent in the OPC assay, in which we can achieve reasonable levels in the brain. So we're currently evaluating those in these preclinical rodent models. And once we demonstrate efficacy there, we'll then go and evaluate their mechanism of action.

MSDF

You test these compounds first in a phenotypic sense to see if they actually do something that you want done. And then you trace it back to mechanism of action?

Dr. Lairson

Correct. That's our general approach for a lot of assays. So rather than looking at a validated, biochemical target, typically we'll just look for small molecules that induce the cell fate decision that we're interested in. For me, personally, it's the most interesting part of the project is I’m figuring out how those compounds that we rule out known mechanisms how they're actually acting. So we do the mass spec-based proteomics to figure out the specific protein target. And then we use standard cellular molecular biology techniques to elucidate the downstream mechanism of action.

MSDF

So I suppose the phenotype you're looking for in the case of this research we've been discussing is remyelination. How do you look for that activity?

Dr. Lairson

The remyelination activity in vitro? We use a co-culture assay, which we collaborate with Rusty Gage at Salk where we pre-differentiate neurons in a dish and then co-culture with our oligodendrocyte precursors plus or minus drug and then look at the ability of those drugs to enhance the rate of myelination of co-cultured axons.

MSDF

And you just stain the cells in vitro looking for myelin production or myelin basic protein?

Dr. Lairson

Exactly, yeah. So we just look at myelin basic protein co-localization with axon.

MSDF

Very good. I appreciate it, thanks.

Dr. Lairson

Absolutely. Thanks very much for your interest.

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MSDF

Thank you for listening to Episode Fifty-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. 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.

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