Multiple Sclerosis Discovery -- Episode 9 with Dr. Amit Bar-Or

[intro music]   Host – Dan Keller Hello, and welcome to Episode Nine of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with researcher Amit Bar-Or about how children with MS can illuminate early mechanisms of the disease. But to begin, here's a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org.   According to a Cochrane meta-analysis, interferon-beta and glatiramer acetate are clinically similar treatments for multiple sclerosis. Researchers analyzed five head-to-head clinical trials and found that both drugs did similarly well in improving disability scores and MRI measures in patients with relapsing remitting MS. The researchers were not able to measure quality of life scores for the disease-modifying therapies.   We also published a Research Roundup this week all about social media and the role it plays in science. Social media can sometimes work against the scientific method if patients in a clinical trial are in the habit of oversharing on blogs, Facebook, or Twitter. Patients who discuss their symptoms online might affect the blinding of clinical trials. It’s not all bad, though. We also wrote about some great social media sites for researchers such as ResearchGate, LinkedIn, and even Reddit. We also shared some amusing links on how scientists can improve their communication skills such as the “Up-Goer Five,” a schematic of the Saturn V rocket explained using only the 1000 most commonly used words in English.   Every week we curate research articles on all topics related to multiple sclerosis and highlight our favorites in the “Editors' Pick.” Last week, some of our favorites were a review on oligodendrocytes, a research article about the origin and maturation of B cells, and a review about how the relationship between axons and myelin is involved in demyelination. You can see our weekly picks by going to our website, clicking on the “Papers” tab, and selecting “Editors’ Picks.” In addition to the Editors’ Picks, we link to every MS-related study found in PubMed. Last week was a banner week for MS studies. One hundred four were published, and we linked to them all.   [transition music]   Now to the interview. Dr. Amit Bar-Or is an associate professor of neurology and neurosurgery at McGill University. Some of his work focuses on multiple sclerosis in children and how they can shed light on the origin of the disease.   Interviewer – Dan Keller Welcome, Dr. Bar-Or. Let's talk about pediatric MS and what we can learn from it, especially about treating children but also about what it tells us about the disease, in general. Where does it stand now? What have you found in children?   Interviewee – Amit Bar-Or Well the last few years have seen a substantial increase in the appreciation that MS can occur, does occur in children. Probably one out of every twenty adults with MS will have had an initial episode clinically that manifested in the pediatric age group, which one defines somewhat arbitrarily as 18 in most places. But the presence of MS in children, of course, you can imagine creates a particularly sensitive clinical context with a lot of challenges to both the child and the family and caregivers. So understanding more about pediatric onset MS – for the purpose of better caring for the children – is one important accomplishment of some of the more recent insights that have been gained in the groups that have been studied. The other, of course, is that a challenge that we have, in general, in the MS field is understanding more about what initiates MS. What are the initiating mechanisms? We've learned a fair bit but still have more to learn about the genetics and about the environmental contributions. And we know that in adults with MS one can measure certain abnormalities, for instance, in their immune response, but we really don’t know whether an abnormality that is measured in an adult represents a consequence of dysregulation and an epiphenomena that may be abnormal but is not going to benefit the illness if you treat it, as opposed to an abnormality that is very much involved in mediating the problem. So the children given that at least, on the average, they're going to be closer to the biological onset of the illness could this provide an opportunity to get insights into earlier mechanisms in a context that is less confounded by such epiphenomena of chronicity, of long-standing illness. And so, one is viewing the studies that are ongoing now – in terms of trying to better understand the pediatric MS context – both in terms of the merits of understanding them for their own sake, as well as a potential window into the broader spectrum. One of the first questions that you then need to ask if you're considering whether children can teach you about MS, in general, is whether MS in children is the same illness as MS in adults. Maybe they're different illnesses. And so one of the approaches that has been taken is to say in adults who develop MS as adults the field has identified certain genetic risk factors and certain environmental exposures that are thought to contribute to risk. And one of the first questions that has been asked is do those same risk factors – genetic and environmental – play out in children who develop MS? And the answer is essentially yes. For the same types of genetic contributors that have been identified in adults, one can see them as risk factors for developing MS in children. And the same environmental exposures – which include, for instance, low levels of vitamin D or exposure to a particular virus called Epstein-Barr virus at a certain phase – these again in children have emerged as being risk factors for the development of MS. So one thinks that at least based on that indirect evidence we can think of pediatric onset MS as, indeed, a reflection of the same illness at earlier time points and again reinforcing the value of understanding early mechanisms less encumbered by chronic disease processes.   MSDF What early mechanisms have you been able to discern from looking at the development of MS in children?   Dr. Bar-Or Well, there are a few very interesting observations that have emerged, and they include observations both on the immune system side and on the central nervous system side. So I'll start with the central nervous system side. We have always been challenged with the effort of trying to understand what are the actual targets of injury in multiple sclerosis. Certainly over the years, it's been described as an illness that affects myelin – the myelin making cells or the oligodendrocytes – so people have considered myelin antigens, or potential targets, as important targets in the disease. But much of that thinking has, in fact, been shaped by the most commonly used animal model system, which is experimental autoimmune encephalomyelitis, where you, in fact, inoculate the animal in its periphery with an antigen of the CNS typically a myelin antigen such as MBP or PLP or MOG. The animal has T cells that then get activated in the periphery that can respond to that antigen. They traffic to the central nervous system, identify the antigen, and contribute to an inflammatory injury process. In MS, though, we do not know what the triggering insult is or what they are in terms of the sequence, and we still don't really know what the actual targets of the illness are. This is important because more and more we've appreciated over the last decade or two that in addition to the myelin and the oligodendrocytes there's a very important injury to the neurons and their axons – the neuronal cell bodies and their extensions where they deliver their signals – which are typically wrapped in some cases in myelin, and others remain demyelinated or lacking in myelin. The issue of what the target is could guide both a better insight into initiating mechanisms – and how to deal with them therapeutically – as well as therapies that are designed to try to target very specific immune responses. Because if we knew what the specific antigens were, we might be able to develop approaches to change the immune system in what's called an antigen-specific way. Which means we try to change only the bad guys' cells or enhance the very specific regulatory cells that will control them without impacting the rest of the immune system, which would be conceptually much better in terms of having both benefit without risks of limiting the ability of the immune system to do, for the most part, what it does normally. One study in which we had the opportunity to compare spinal fluids from children presenting with a first episode of what may or may not be MS, and these children are then followed very, very carefully prospectively – meaning forward in time – as part of the Canadian Pediatric Demyelinating Disease Study was to establish over time who, in fact, has MS and who doesn't. And then go back to those early samples from that first clinical event and compare it what's called a proteomic level where we say we don’t know what the differences might be, but let's use a technology that breaks the CSF down – the cerebrospinal fluid down – into all of the components that make the different proteins. And then we have a survey of all of the different protein content and compare between the two. And we anticipated that we would see differences in those typical myelin antigens that the community has thought over the years are the relevant targets. So first surprise was we did not see any differences in those particular previously or traditionally implicated antigens. However, we did see differences in a number of molecules that are referable to a tiny little apparatus that serves an important physiologic function, and that's called the axoglial apparatus. That area is a tiny, tiny area where the glial cell – in this case the oligodendrocyte, the myelinating cell – its membrane dives down and attaches to the axon. That point of contact is part of what forms the axoglial apparatus. And it becomes a very enticing potential target of injury because an injury to that target would be expected to cause, on one hand, injury to the myelinating cell (maybe leading to demyelination) but also could produce an injury to the axon itself perhaps contributing to the axonal and neuronal injury. And again, we now know that both of those injuries are very much part of the MS disease process, or at least part of the consequence of the MS disease process. So this is just one study in children where we may be getting clues in a more refined way to the particular early targets of the disease or those structures involved in early in the disease, which is now guiding some of the thinking about how to followup on that both to better understand and potentially target therapeutically. An example on the immune system side is that there has been the sense in the broad community in MS and in other human autoimmune conditions that certain types of cells – that are called effector cells – may be dysregulated in MS either because they are overly active or insufficiently regulated or both. So either an effector problem, a regulator problem, or a combination of the two. But it's been difficult to identify which of these cell subsets is really involved in the disease as opposed to dysregulated, as I mentioned before, as a consequence of the disease. And the children have provided an opportunity to again look early on. And one study had identified that one of the abnormalities had appeared to involve a failure of normally developing regulatory T cells – this is work by Regitta Walderman (12:20) and Betina Belint at the time – which showed very nicely that in children with MS, as compared to controls, there seems to be a deficiency in the development or the maintenance of regulatory T cells. And in fact, it looked as though cells that normally get educated by an organ that we call the thymus, which is very active particularly in children, seemed to be getting older faster in the kids with MS. And so this raises the interesting question of whether there is a premature senescence or premature aging, in a sense, of certain immune cell populations so that over time their functional capacity is not quite the same, and if this is on the regulatory cell side and you have a diminished capacity for whatever reason you might expect the effector cells to be able to spillover inappropriately and participate in disease. So those are two examples – one of the neurobiological side and one of the immunological side – where children are providing what I would consider very important insights into the overall MS spectrum.   MSDF Let me ask you about the injury to the axoglial complex. Glia provide supporting roles both nutritionally and through other molecules and as well as physically. Do you think this is an injury to the oligodendrocyte – which then impacts the axon – or is it some sort of attack which just hits this area, in general?   Dr. Bar-Or Well this is a great question. And there's an ongoing discussion as to the chicken/egg; what gets injured first? What we do know is that when you look at the available tissue for studying pathology of MS – which, of course, tends to be quite biased to late in the disease where people may die for other reasons and postmortem – we have relatively little insight pathologically in what's happening in patients in early stages of the disease. Fortunately, people who develop MS even through the diagnosis rarely, rarely require a biopsy to get tissue to establish the diagnosis. And in fact, if you're doing a biopsy, it's usually because it's atypical, not typical. So we have several groups who are working hard and making important contributions, including into this earlier event, but there is still a big gap in our understanding of the early events and hence the very difficult to talk about initiating processes. But you bring up the very important context of the neurobiology of MS, which involves the ongoing function and integrity of the brain cells, including the neurons and the different glial cells. Those include the oligodendrocytes which make myelin but also the astrocytes which provide, among other things, important support to the blood-brain barrier and important support to the neurons, as well as the microglial cells which are very crafty cells of the central nervous system that probably performs several different functions. And all of these cells when they get activated or insulted they may fail to provide the normal physiologic protection, or they may even actively contribute to propagating injury. If you injure the oligodendrocyte in the myelin, the axon that is served by that myelin is working harder and may peter out over time. On the other hand, the integrity of the axon is important for the oligodendrocyte to maintain its myelination and its wrapping (15:34). So there's very important crosstalk, and it is very likely that injuring one element sufficiently will result in deterioration of the other regardless of which one you're injuring first. From a therapeutic standpoint, our efforts are to understand this crosstalk better and to understand how to try to establish protection, if not repair, of any one of these elements as part of the overview. It's clear that if you don't have an axon there's nothing to myelinate; if you don't have the myelinating cells you're left with bare axons that don't function or survival as well with the increased demand. And so, we need to have a more complete view so that we can approach not just a single biology at a time but, of course, we also – to understand any given biology – have to develop approaches that will isolate that biology so we can understand it. And one of our challenges is that we do not really have good models of those neurobiological aspects of MS to study. The EAE, for instance, which recapitulates some of the features of MS, has not really been shown to recapitulate those particular features that we're discussing.   MSDF Finally, let me get back to one thing you mentioned that if you can identify the antigens of interest that are either spurring an attack or being targets of an attack the idea would be to find specific ways to approach those antigens. Now we have certain drugs that will deplete B cells, and they show benefit. We have certain drugs that will keep trafficking down cell adhesion molecules, and those seem to have benefit. Is there a focus on any particular antigens at this point and any particular approaches (clonal deletion, any sort of small molecules)? Where's that going?   Dr. Bar-Or Well there are a number, and I probably won't be able to summarize all of them here. But there are generally several different strategies that try to target the immune system in a much more selective way than most of the approved therapies, including the not yet approved B-cell depleting approach which, of course, is more specific than targeting cells beyond B cells but is still depleting quite a few cells. Many of the B cells in the circulation, at least, are depleted. One extension to what you had raised is that it's fascinating to see how different approaches can achieve benefit of decreasing new disease activity, and we need to be able to sit back on a regular basis and integrate the insights from all of the successful, as well as unsuccessful, therapeutic interventions, including those that were not only unsuccessful in limiting new disease activity but the occasion where they increased new disease activity. What would appear initially paradoxical. Understanding all of that will give us very important insights into the disease itself. As far as antigen-specific approaches, one way is if you know what the antigen is – which, of course, we don't really know but we can hypothesize – you can try to develop induction of regulatory cells with that specificity or killing off or creating a state of unresponsiveness, also know as (18:40) of the effector specific cells or a combination of the two. There are different strategies that people have tried to use that are based, for instance, on the requirement of a T cell during activation to have an antigen-presenting cell present the antigen. And the profile of molecules both through contact and through secretion that the T cell can then receive in that environment of interaction with the antigen-presenting cell can often define the response profile, subsequently, of that cell. And if certain molecules such as costimulatory molecules are not present in that interaction or modulated, you might actually shut the cell down – you may not kill it, but it will be unresponsive or hyperresponsive – and that would be one strategy. Another, for instance, is to say well I don't know exactly which particular antigen, but I think it's myelin antigens. Let me get out of a patient's blood their immune cells and stimulate them to a variety of potential antigens, and whatever grows will reflect what grows in that person against the CNS antigens. And use that in a way to modify them so that they cannot cause problems and inject them back into a patient almost like a vaccine with a view that you are now giving that person whatever their T cells were that could respond to myelin, and their immune system now will respond to them and kill them and kill any other such cells that are present in the body leaving the rest of the immune system intact. And will that limit that person's ability to respond to their myelin? That again, is individualized medicine, which is one of the hot areas to pursue in the future, recognizing that if we hang our hat on a single target that may be true for one person but not for others or may be true for a person at some point in their illness but is not the predominant target later on. And so I think that using these kinds of approaches, which recognize the specificity or the selectivity, at least, as potential but also that there are very likely to be differences across individuals and maybe even with the same individual over time. And to try to individualize the therapy that is going to be most suitable for that person at that time.    MSDF Thank you, Dr. Bar-Or.   [transition music]   Thank you for listening to Episode Nine of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to [email protected].   [outro music]