Info

Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum

Your independent source of news and information on research in multiple sclerosis and related diseases.
RSS Feed
Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum
2018
April
January


2016
September
August
July
June
May
April
March
February
January


2015
December
November
October
September
August
July
June
May
April
March
February
January


2014
December
November
October
September
August
July
June


All Episodes
Archives
Now displaying: September, 2014
Sep 29, 2014

[intro music]

 

Host – Dan Keller

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

 

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

 

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

 

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

 

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

 

[transition music]

 

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

 

Interviewer – Dan Keller

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

 

Interviewee – Gavin Giovannoni

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

 

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

 

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

 

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

 

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

 

MSDF

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

 

Dr. Giovannoni

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

 

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

 

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

 

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

 

MSDF

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

 

Dr. Giovannoni

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

 

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

 

MSDF

Does it get into the possibility of tolerance?

 

Dr. Giovannoni

Yes.

 

MSDF

To EBV?

 

Dr. Giovannoni

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

 

MSDF

Very good. Thank you.

 

[transition music]

 

MSDF

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

 

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

 

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

 

[outro music]

 

 

 

 

 

Sep 22, 2014

[intro music]

 

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

 

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

 

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

 

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

 

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

 

[transition music]

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

Interviewer – Cynthia McKelvey

What is the goal of the Progressive MS Alliance?

 

Interviewee – Dr. Alan Thompson

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

 

MSDF

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

 

Dr. Thompson

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

 

MSDF

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

 

Dr. Thompson

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

 

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

 

MSDF

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

 

Dr. Thompson

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

 

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

 

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

 

MSDF

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

 

Dr. Thompson

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

 

MSDF

Why is it challenging to study that scientifically?

 

Dr. Thompson

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

 

MSDF

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

 

Dr. Thompson

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

 

MSDF

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

 

Dr. Thompson

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

 

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

[transition music]

 

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

 

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

 

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

 

 [outro music]

 

 

 

 

Sep 15, 2014

[intro music]

 

Host – Dan Keller

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

 

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

 

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

 

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

 

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

 

[transition music]

 

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

 

Interviewer – Dan Keller

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

 

Interviewee – Gavin Giovannoni

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

 

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

 

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

 

MSDF

Now these are autologous bone marrow transplants?

 

Dr. Giovannoni

Yes.

 

MSDF

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

 

Dr. Giovannoni

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

 

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

 

MSDF

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

 

Dr. Giovannoni

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

 

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

 

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

 

MSDF

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

 

Dr. Giovannoni

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

 

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

 

MSDF

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

 

Dr. Giovannoni

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

 

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

 

MSDF

Is chemotherapy in itself a reasonable treatment?

 

Dr. Giovannoni

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

 

MSDF

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

 

Dr. Giovannoni

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

 

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

 

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

 

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

 

MSDF

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

 

Dr. Giovannoni

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

 

MSDF

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

 

Dr. Giovannoni

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

 

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

 

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

 

MSDF

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

 

Dr. Giovannoni

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

 

MSDF

If you look long enough.

 

Dr. Giovannoni

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

 

MSDF

Locking the barn door while the horse is still in.

 

Dr. Giovannoni

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

 

MSDF

Very good. We appreciate it. Thank you.

 

[transition music]

 

MSDF

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

 

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

 

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

 

[outro music]

 

 

Sep 8, 2014

[intro music]

 

Host – Dan Keller

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

 

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

 

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

 

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

 

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

 

[transition music]

 

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

 

Interviewer – Dan Keller

Welcome, Dr. Antel.

 

Interviewee – Jack Antel

Thank you very much.

 

MSDF

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

 

Dr. Antel

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

 

MSDF

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

 

Dr. Antel

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

 

MSDF

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

 

Dr. Antel

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

 

MSDF

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

 

Dr. Antel

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

 

MSDF

How does all of this relate to progressive MS?

 

Dr. Antel

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

 

MSDF

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

 

Dr. Antel

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

 

MSDF

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

 

Dr. Antel

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

 

MSDF

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

 

Dr. Antel

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

 

MSDF

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

 

Dr. Antel

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

 

MSDF

Very good. We appreciate it.

 

Dr. Antel

My pleasure.

 

[transition music]

 

MSDF

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

 

 

Host – Dan Keller

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

 

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

 

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

 

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

 

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

 

[transition music]

 

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

 

Interviewer – Dan Keller

Welcome, Dr. Antel.

 

Interviewee – Jack Antel

Thank you very much.

 

MSDF

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

 

Dr. Antel

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

 

MSDF

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

 

Dr. Antel

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

 

MSDF

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

 

Dr. Antel

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

 

MSDF

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

 

Dr. Antel

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

 

MSDF

How does all of this relate to progressive MS?

 

Dr. Antel

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

 

MSDF

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

 

Dr. Antel

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

 

MSDF

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

 

Dr. Antel

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

 

MSDF

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

 

Dr. Antel

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

 

MSDF

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

 

Dr. Antel

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

 

MSDF

Very good. We appreciate it.

 

Dr. Antel

My pleasure.

 

[transition music]

 

MSDF

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

 

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

 

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

 

[outro music]

 

 

Schmidt is vice president of scientific operations.

 

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

 

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

 

[outro music]

 

 

Sep 1, 2014

[intro music]

 

Host – Dan Keller 

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

 

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

 

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

 

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

 

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

 

[transition music]

 

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

 

Interviewee – Richard Ransohoff

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

 

Interviewer – Carol Morton

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

 

Dr. Ransohoff

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

 

MSDF

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

 

Dr. Ransohoff

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

 

MSDF

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

 

Dr. Ransohoff

Are there other ways of looking at it?

 

MSDF 

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

 

Dr. Ransohoff

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

 

MSDF 

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

 

Dr. Ransohoff

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

 

MSDF

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

 

Dr. Ransohoff

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

 

MSDF 

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

 

Dr. Ransohoff

Oh, thank you. 

 

[transition music]

 

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

 

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

 

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

 

[outro music] 

 

1