Hans Lassmann's guest appearances

Hans Lassmann

Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum

Alan Alda

Tim Kennedy

Richard Cohen

David Baker

Jeffrey Cohen

Michael Levy

Alan Thompson

David Holtzman

Oscar Fernandez

Paul Matthews

Raj Kapoor

Adam Kaplin

Bruce Cree

Lilyana Amezcua

Daniel Hartung

OwlTail

[intro music]   Host – Dan Keller Hello, and welcome to Episode Forty-Seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features the second part of a two-part interview with Dr. Hans Lassmann, who discusses oxidative stress as a mechanism of tissue injury in progressive MS. But first, here are some of the new items in the MS Discovery Forum.   According to our curated list of the latest scientific articles related to MS, 56 such articles were published last week. To see the list, go to msdiscovery.org and click on Papers. We selected two of those papers as Editors’ Picks. One of them includes revised guidelines from the Association of British Neurologists on prescribing disease-modifying treatments for MS. The other describes an international consensus on diagnostic criteria for neuromyelitis optica and related disorders.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the month of June, we added 10 new trials, we updated information on 6 other trials, and we’ve added 67 other pieces of information. The drugs with important additions and changes are alemtuzumab, cladribine, cyclophosphamide, daclizumab, dalfampridine, dimethyl fumarate, fingolimod, glatiramer acetate, idebenone, interferon beta-1a, interferon beta-1b, laquinimod, rituximab, natalizumab, and ocrelizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.   [transition music]   Now to our interview with Dr. Hans Lassmann of the Medical University of Vienna in Austria. Last week we spoke about biomarkers, and this week we’ll discuss oxidative stress as a mechanism of tissue injury in progressive MS.   Interviewer – Dan Keller What's interesting there at this point?   Interviewee – Hans Lassmann The big problem in multiple sclerosis is that we have very good therapies for the early stage of multiple sclerosis, and they all interfere with the inflammation and the immune system. But when the patients have reached a progressive stage of the disease, then all these therapies are currently noneffective. So the key points were to define what are actually the mechanisms of inflammation and tissue injury in the progressive stage of multiple sclerosis, and there are still a lot of open questions. It is clear that even in the progressive stage there is an inflammatory process, and this inflammatory process is associated with active tissue damage. From that certainly we cannot definitely conclude that the inflammatory process drives the tissue damage; however, it's clearly associated.   Now, we were then very interested to see what are the mechanisms of tissue injury. And this involves, first of all, studies on the nature of the inflammatory process. And here what we found is that in the progressive stage of multiple sclerosis the inflammatory reaction is predominantly hidden within the central nervous system behind a repaired blood-brain barrier. So that means this inflammatory process is no longer really under control of the peripheral immune system. And also, the therapies which we have currently mainly interfere with immune functions in the periphery, and they have actually very little access to an inflammatory process which is taking place within the central nervous system.   So that means that new drugs have to be developed and tested which actually exert an antiinflammatory or some neuroprotective action directly within the central nervous system. And there are now a number of the large companies fully engaged in this process, and there are new candidates coming up, which will have to be tested in proper clinical trials in patients with progressive MS.   The second question, which we have mainly addressed during the last year, was the mechanisms how the tissue damage is induced. And in this regard, we concentrated on cortical lesions in multiple sclerosis, which are very, very specific for the disease. And we compared in gene expression studies these cortical lesions not only with normal controls but also with inflammatory controls. And we used here a disease which has very similar inflammatory infiltrates, as you see in multiple sclerosis brain, but doesn't lead to the MS typical demyelination, and this is tuberculous meningitis. And then we also used as a control for neurodegeneration Alzheimer's disease just to see what is a reaction in gene expression due to degeneration of neurons.   And when we did that, actually it was interesting to see that there were relatively few genes which were specifically changed in their expression in multiple sclerosis patients in comparison to these other disease controls. And these genes were, in part, associated with inflammatory processes. A large part of the genes were associated with a more or less single pathway of tissue injury, which includes oxidative injury leading to mitochondrial injury and its secondary consequences. And then, there were also some genes involved which were MS specifically related to tissue regenerative processes.   We have then looked in further detail, and it now turns out that this cascade of oxidative injury leading to mitochondrial dysfunction and with that to a state of energy deficiency is actually one of the major driving forces of neurodegeneration in the progressive stage of multiple sclerosis. So this oxidative injury is, in part, driven by the inflammatory process. But it is also augmented by factors which are related to age of the patients and to the accumulation of lesion burden due to the chronic disease.   So here the central portion is the activation of microglial cells which can, on the one hand, be activated in the inflammatory process, but they also get activated when tissue is damaged due to completely different causes. And they also get activated just simply in an aging process. And in this respect, then they get activated in a pro-oxidative form. And then, the tissue injury can further be propagated through additional age-related changes, including, for instance, the accumulation of iron in the central nervous system and also obviously the chronic microglia activation due to retrograded and anterograde degeneration when lesions already present within the central nervous system.   MSDF Are the microglia just overdoing what they normally would be expected to do? I mean macrophages use oxidative systems to get rid of pathogens.   Dr. Lassmann Yeah, this is absolutely true. That is a key element of microphage and microglia function. And this is exaggerated in both the aging process, as well as in the chronic inflammatory state like multiple sclerosis. The question only remains what is really driving this massive microglia activation in MS, which is even more and more pronounced than even in very severe other inflammatory diseases of the central nervous system.   MSDF Can you identify or has anyone identified factors that disappear with aging or are increased with aging that may lead to this state?   Dr. Lassmann That is also not really very clear now. I think one interesting aspect is that this massive microglia activation in the direction of oxidative stress you don't really see in rodents and even not in primate experimental models; you see it in humans. And the reason for that is not completely clear, but it may very well be that environmental factors actually play a major role. I think one of the major differences between humans and these experimental animals is that the experimental animals are genetically very homogenous; they are generally inbred strains. And the second is that they are kept under a very constant pathogen-free environment. And this is very different in a human situation, and these animals also have a very … standardized diet. Now this is completely different in human situations, and there are certainly many factors, including peripheral infections but also including diet changes, and many other factors can actually have an influence on microglia in the central nervous system.   MSDF And experimental animals also have optimized diets; people have figured out the nutrients they need I suppose. They're getting a good diet compared to people who knows how everybody is eating these days.   Dr. Lassmann Yes, that's absolutely the case. They have a standardized diet, and they certainly are not exposed to very much of the fats, for instance, which we take into when we eat fat pork meat.   MSDF Do any of the antiinflammatory agents modify the course? Things like lipoxygenase inhibitors and things like that? Not necessarily NSAIDs but now that you bring up fats?   Dr. Lassmann I think there is certainly an aspect behind that is that lifestyle control certainly has a beneficial effect. One can just see that in a way that environmental lifestyle factors, which actually also increase the risk for vascular injury or other things, will be certainly deleterious in a patient with progressive multiple sclerosis where the brain is already damaged due to the original disease process and where the functional reserve capacity of the brain is already partially exhausted. So in that case, even minor changes – which are related to lifestyle or aging – will have a more dramatic effect in such a brain than in a normal aging brain.   MSDF Finally, circling back to something you said at the beginning, in progressive MS I think you said that the immune system the cells have now entered the brain, but the blood-brain barrier has – once again – become a real barrier. So do you really have an immune response running autonomously in the brain no longer subject to any sort of peripheral control?   Dr. Lassmann Yeah, this is certainly a very important open question. We know that the inflammatory cells are present within the central nervous system in the progressive stage and that they are associated with the degenerative processes and the demyelination. We know currently very little about the exact phenotype and functional activation of the inflammatory cells within the central nervous system. This is actually a large research project, which is running currently in my lab, to try to define exactly the functional polarization of the cells within the MS lesions and to determine their activation state, their proliferation rate, and so on.   What we can say from our preliminary data on that is that they are present, they are in part activated. They also express certain transcription factors, which would be associated with a proinflammatory state in the central nervous system. However, overall all these changes are relatively small in comparison to an acute, for instance, virus-induced inflammatory process in the brain. So it seems to be that there is a slow and low-grade activation state which, however, could be completely sufficient to drive the degenerative process in the patients. But that is not the final answer yet.   [transition music]   MSDF Thank you for listening to Episode Forty-seven of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.    Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.   [outro music]

[intro music] Host – Dan Keller Hello, and welcome to Episode Forty-Seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller. This week’s podcast features the second part of a two-part interview with Dr. Hans Lassmann, who discusses oxidative stress as a mechanism of tissue injury in progressive MS. But first, here are some of the new items in the MS Discovery Forum. According to our curated list of the latest scientific articles related to MS, 56 such articles were published last week. To see the list, go to <a href="http://msdiscovery.org" rel="nofollow" target="_blank">msdiscovery.org</a> and click on Papers. We selected two of those papers as Editors’ Picks. One of them includes revised guidelines from the <a href="http://www.msdiscovery.org/papers/biblio/19772-association-british-neurologists-revised-2015-guidelines-prescribing-disease" rel="nofollow" target="_blank">Association of British Neurologists</a> on prescribing disease-modifying treatments for MS. The other describes an international consensus on diagnostic criteria for neuromyelitis optica and related disorders. Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the month of June, we added 10 new trials, we updated information on 6 other trials, and we’ve added 67 other pieces of information. The drugs with important additions and changes are alemtuzumab, cladribine, cyclophosphamide, daclizumab, dalfampridine, dimethyl fumarate, fingolimod, glatiramer acetate, idebenone, interferon beta-1a, interferon beta-1b, laquinimod, rituximab, natalizumab, and ocrelizumab. To find information on all 44 compounds, visit <a href="http://msdiscovery.org" rel="nofollow" target="_blank">msdiscovery.org</a> and click first on Research Resources and then on Drug-Development Pipeline. [transition music] Now to our interview with Dr. Hans Lassmann of the Medical University of Vienna in Austria. Last week we spoke about biomarkers, and this week we’ll discuss oxidative stress as a mechanism of tissue injury in progressive MS. Interviewer – Dan Keller What's interesting there at this point? Interviewee – Hans Lassmann The big problem in multiple sclerosis is that we have very good therapies for the early stage of multiple sclerosis, and they all interfere with the inflammation and the immune system. But when the patients have reached a progressive stage of the disease, then all these therapies are currently noneffective. So the key points were to define what are actually the mechanisms of inflammation and tissue injury in the progressive stage of multiple sclerosis, and there are still a lot of open questions. It is clear that even in the progressive stage there is an inflammatory process, and this inflammatory process is associated with active tissue damage. From that certainly we cannot definitely conclude that the inflammatory process drives the tissue damage; however, it's clearly associated. Now, we were then very interested to see what are the mechanisms of tissue injury. And this involves, first of all, studies on the nature of the inflammatory process. And here what we found is that in the progressive stage of multiple sclerosis the inflammatory reaction is predominantly hidden within the central nervous system behind a repaired blood-brain barrier. So that means this inflammatory process is no longer really under control of the peripheral immune system. And also, the therapies which we have currently mainly interfere with immune functions in the periphery, and they have actually very little access to an inflammatory process which is taking place within the central nervous system. So that means that new drugs have to be developed and tested which actually exert an antiinflammatory or some neuroprotective action directly within the central nervous system. And there are now a number of the large companies fully engaged in this process, and there are new candidates coming up, which will have to be tested in proper clinical trials in patients with progressive MS. The second question, which we have mainly addressed during the last year, was the mechanisms how the tissue damage is induced. And in this regard, we concentrated on cortical lesions in multiple sclerosis, which are very, very specific for the disease. And we compared in gene expression studies these cortical lesions not only with normal controls but also with inflammatory controls. And we used here a disease which has very similar inflammatory infiltrates, as you see in multiple sclerosis brain, but doesn't lead to the MS typical demyelination, and this is tuberculous meningitis. And then we also used as a control for neurodegeneration Alzheimer's disease just to see what is a reaction in gene expression due to degeneration of neurons. And when we did that, actually it was interesting to see that there were relatively few genes which were specifically changed in their expression in multiple sclerosis patients in comparison to these other disease controls. And these genes were, in part, associated with inflammatory processes. A large part of the genes were associated with a more or less single pathway of tissue injury, which includes oxidative injury leading to mitochondrial injury and its secondary consequences. And then, there were also some genes involved which were MS specifically related to tissue regenerative processes. We have then looked in further detail, and it now turns out that this cascade of oxidative injury leading to mitochondrial dysfunction and with that to a state of energy deficiency is actually one of the major driving forces of neurodegeneration in the progressive stage of multiple sclerosis. So this oxidative injury is, in part, driven by the inflammatory process. But it is also augmented by factors which are related to age of the patients and to the accumulation of lesion burden due to the chronic disease. So here the central portion is the activation of microglial cells which can, on the one hand, be activated in the inflammatory process, but they also get activated when tissue is damaged due to completely different causes. And they also get activated just simply in an aging process. And in this respect, then they get activated in a pro-oxidative form. And then, the tissue injury can further be propagated through additional age-related changes, including, for instance, the accumulation of iron in the central nervous system and also obviously the chronic microglia activation due to retrograded and anterograde degeneration when lesions already present within the central nervous system. MSDF Are the microglia just overdoing what they normally would be expected to do? I mean macrophages use oxidative systems to get rid of pathogens. Dr. Lassmann Yeah, this is absolutely true. That is a key element of microphage and microglia function. And this is exaggerated in both the aging process, as well as in the chronic inflammatory state like multiple sclerosis. The question only remains what is really driving this massive microglia activation in MS, which is even more and more pronounced than even in very severe other inflammatory diseases of the central nervous system. MSDF Can you identify or has anyone identified factors that disappear with aging or are increased with aging that may lead to this state? Dr. Lassmann That is also not really very clear now. I think one interesting aspect is that this massive microglia activation in the direction of oxidative stress you don't really see in rodents and even not in primate experimental models; you see it in humans. And the reason for that is not completely clear, but it may very well be that environmental factors actually play a major role. I think one of the major differences between humans and these experimental animals is that the experimental animals are genetically very homogenous; they are generally inbred strains. And the second is that they are kept under a very constant pathogen-free environment. And this is very different in a human situation, and these animals also have a very … standardized diet. Now this is completely different in human situations, and there are certainly many factors, including peripheral infections but also including diet changes, and many other factors can actually have an influence on microglia in the central nervous system. MSDF And experimental animals also have optimized diets; people have figured out the nutrients they need I suppose. They're getting a good diet compared to people who knows how everybody is eating these days. Dr. Lassmann Yes, that's absolutely the case. They have a standardized diet, and they certainly are not exposed to very much of the fats, for instance, which we take into when we eat fat pork meat. MSDF Do any of the antiinflammatory agents modify the course? Things like lipoxygenase inhibitors and things like that? Not necessarily NSAIDs but now that you bring up fats? Dr. Lassmann I think there is certainly an aspect behind that is that lifestyle control certainly has a beneficial effect. One can just see that in a way that environmental lifestyle factors, which actually also increase the risk for vascular injury or other things, will be certainly deleterious in a patient with progressive multiple sclerosis where the brain is already damaged due to the original disease process and where the functional reserve capacity of the brain is already partially exhausted. So in that case, even minor changes – which are related to lifestyle or aging – will have a more dramatic effect in such a brain than in a normal aging brain. MSDF Finally, circling back to something you said at the beginning, in progressive MS I think you said that the immune system the cells have now entered the brain, but the blood-brain barrier has – once again – become a real barrier. So do you really have an immune response running autonomously in the brain no longer subject to any sort of peripheral control? Dr. Lassmann Yeah, this is certainly a very important open question. We know that the inflammatory cells are present within the central nervous system in the progressive stage and that they are associated with the degenerative processes and the demyelination. We know currently very little about the exact phenotype and functional activation of the inflammatory cells within the central nervous system. This is actually a large research project, which is running currently in my lab, to try to define exactly the functional polarization of the cells within the MS lesions and to determine their activation state, their proliferation rate, and so on. What we can say from our preliminary data on that is that they are present, they are in part activated. They also express certain transcription factors, which would be associated with a proinflammatory state in the central nervous system. However, overall all these changes are relatively small in comparison to an acute, for instance, virus-induced inflammatory process in the brain. So it seems to be that there is a slow and low-grade activation state which, however, could be completely sufficient to drive the degenerative process in the patients. But that is not the final answer yet. [transition music] MSDF Thank you for listening to Episode Forty-seven of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. [outro music]

Multiple Sclerosis Discovery -- Episode 47 with Dr. Hans Lassmann (Part 2)

Hello, and welcome to Episode Forty-Six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features the first part of a two-part interview with Dr. Hans Lassmann, who discusses biomarkers in multiple sclerosis. But first, here are some of the new items in the MS Discovery Forum.   According to our curated list of the latest scientific articles related to MS, 61 such articles were published last week. To see the list, go to msdiscovery.org and click on Papers. We selected two of those papers as Editors’ Picks. One, on the prevalence of pain in MS, found that around two-thirds of MS patients experience pain, and this symptom is associated with disability, depression, and especially anxiety. The other editor’s pick is a study of a toxin produced by Clostridium perfringens, a common bacterium often found in the gut that produces an MS-like disease in sheep. This epsilon toxin selectively kills oligodendrocytes while preserving all other neural elements.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week we added 2 new trials and 5 other pieces of information. The drugs with important additions are dalfampridine, dimethyl fumarate, and fingolimod. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline    [transition music]   Now to the interview. Dr. Hans Lassmann of the Medical University of Vienna in Austria, is one of the most prolific and highly respected MS researchers in the world. In this first part of a two part interview, Dr. Lassmann discusses biomarkers in MS and related conditions such as neuromyelitis optica and how the two conditions may differ important for therapy.   Interviewer – Dan Keller Let’s talk about new markers in MS or differentiating conditions from MS. What’s coming along, and what do we know now?   Interviewee – Hans Lassmann Well, there has been a very important development during the last years. And this was the technical development of assays which can really identify pathogenic autoantibodies which can modify the inflammatory process in the central nervous system. The major trick behind was that these assays are, in essence, based on cells which are transfected with the respective antigen, and so they express the respective antigen on the surface of the cell. And one can now identify those autoantibodies which really bind to the surface of the cell and are pathogenic, in comparison to those antibodies which recognize epitopes, for instance, within the cells, which cannot be reached by the antibodies in the in vivo situation, and which, therefore, are not pathogenic.   MSDF Can you give me some examples of these kinds of antibodies?   Dr. Lassmann So the first antibody which was the antibody against aquaporin 4, which has been shown to be associated with neuromyelitis optica, at least with a large fraction of patients with neuromyelitis optica. And this antibody then was very well characterized, and it turned out that it is directed against aquaporin 4, which is a water channel in astrocytes. And when patients have these antibodies on the background of an inflammatory disease in the central nervous system, these antibodies can reach their astrocytic targets and destroy the astrocytes, which then leads to secondary demyelination and neurodegeneration.   Having these antibodies, it was then possible to define the clinical spectrum of the disease, and it turned out that it is very strictly associated with neuromyelitis optica, but that the spectrum of the disease is broader than only affecting the spinal cord and the optic nerve. So these patients actually have also lesions in other regions of the brain. But they are still different from those lesions which you see multiple sclerosis.   It was then also possible to define the clinical spectrum of the disease. And, again, differences to multiple sclerosis became very clear. And, finally, it was also possible to then look in these patients with these aquaporin 4 antibodies how they respond to the current treatment strategies which have been established for multiple sclerosis. And it turned out that several of the key therapies for multiple sclerosis, including interferons but also natalizumab or fingolimod, can actually make the disease worse in patients with neuromyelitis optica.    So that was the first example that a disease which has originally been defined as a disease in the spectrum of multiple sclerosis has emerged as a separate and distinguishable disease which requires also different treatment in the patients.   MSDF It seems like neuromyelitis optica has components of autoimmune disease. So why do these compounds that work in MS potentially make the condition worse in NMO?   Dr. Lassmann This is currently not yet clear. One possibility is that the action of pathogenic antibodies makes the difference. The immune mechanisms are certainly different in a purely T-cell mediated disease, in comparison to disease which is mediated by a combination of T-cells and antibodies. And that could possibly explain why differences are seen.    There is another possibility is that some of these drugs actually stimulate the B-cell response or increase the B-cell response in the peripheral blood, and with that possibly also the antibody response. So, in that case, the T-cell mediated inflammation would be suppressed, but the antibody-mediated effects would be enhanced. And that could certainly also play a role. But these are, at the present moment, not proven.   MSDF But even in MS there’s evidence for B-cell trafficking and B-cell participation, but it seems to be less important or am I off base?   Dr. Lassmann No, this is a very interesting question. There is clearly a B-cell component in multiple sclerosis, and it has also been shown that depleting B-cells, for instance, with an antibody against CD20 can actually have a very good therapeutic effect in multiple sclerosis. However, we have to keep in mind that B-cells not only produce antibodies, but they have also other immunological functions. So one function, for instance, is that they help the T-cells, for instance, by very efficient antigen presentation. So by eliminating B-cells, you get also a decrease of the T-cell response. But this is not only one possibility. There are other possibilities that B-lymphocytes actually can also produce cytokines – proinflammatory cytokines – which may directly act on the tissue and damage the tissue independent from antibodies.   MSDF Getting back to NMO, if someone tests negative for antibody, but has clinical signs, does that rule out NMO or are you just not detecting antibodies or is it always required or not?   Dr. Lassmann So it rules out an aquaporin 4 antibody associated form of NMO, but a fraction of NMO patients – it’s around between 10 and 20% – which have a clinical presentation of NMO, but have no antibodies against aquaporin 4. There is currently very much effort to define what is the mechanism in these patients. And it turned out that a fraction of these aquaporin 4 antibody-negative NMO patients actually have antibodies against myelin oligodendrocyte glycoprotein.    And this leads, actually now, to a second type of disease which can be separated from multiple sclerosis. These are patients with high titers of pathogenic antibodies against myelin oligodendrocyte glycoprotein. Now, again, these patients, when you look at them at pathology, you would clearly define the disease as multiple sclerosis because they have inflammation, and they have very selective primary demyelination. And this is different from what you see in NMO where the astrocyte pathology is the earliest event. But in those patients with the MOG antibodies, its demyelination sort of hallmark, actually, of multiple sclerosis…of the disease process in multiple sclerosis.   However, when you now analyze these patients with mock antibodies, clinically you see that the clinical presentation is different from the classical presentation of multiple sclerosis patients. These antibodies are, for instance, frequent in children with inflammatory demyelinating disease of a spectrum of acute disseminated encephalomyelitis or relapsing disseminated encephalomyelitis or even patients with a disease similar to relapsing, remitting multiple sclerosis. This is in children.   In adults, you find these antibodies in a fraction of NMO patients. But there are also other patients who have a disease which is more similar to what is seen in multiple sclerosis, with the exception that they have relatively large and aggressive lesions, and also that they have, relatively frequently, lesions in the brain stem such as, for instance, the pons or the medulla oblongata. And, again, it seems to be that here a new disease entity appears which can be separated from multiple sclerosis.   Regarding therapy of these patients, we don’t have yet the data which we need to have. It can be speculated that the therapeutic response may possibly be more similar to those patients with NMO in comparison to the classical MS patients, but to know that we would have to have much larger cohorts of patients who have been treated with the different regimes.   MSDF Do some of these do worse on the typical MS treatments such as natalizumab or fingolimod?   Dr. Lassmann These data currently are not yet existing. It’s also because, due to these possible problems related to NMO, generally now, patients with mock-antibody-associated diseases are more likely to be treated with global immunosuppression or with rituximab, so the anti-CD20 antibody. And clinicians are very reluctant to use these therapies which have been shown to make disease worse in NMO in these mock patients. So we don’t have the data, currently.   MSDF Are there separate etiologies, does it look like here, the MOG versus classical MS?   Dr. Lassmann This comes to the important question about the etiology of MS in general. We have to admit that we don’t know what is the real etiology of multiple sclerosis. It is thought to be an autoimmune disease, but this is not finally proven. It may also be associated with infections – Epstein-Barr virus infection is, for instance, one possible example. And there are certainly other theories also, which discuss completely different mechanisms of disease pathogenesis in multiple sclerosis. It is clearly that all these diseases, including NMO, mock antibody associated disease, and MS are chronic inflammatory diseases. But what drives the inflammation is currently not yet known.   MSDF Is it possible there’s an initial insult to oligodendrocytes which then sort of precipitate a chain reaction cascade?   Dr. Lassmann This is also one of the theories which is put forward, but one has to say that with a bit caution, because there are experimental models where you can actually destroy oligodendrocytes in the central nervous system which do not lead to an autoimmune disease which is somehow related or similar to multiple sclerosis.   MSDF Anything interesting or important to add on the subject, in this context?   Dr. Lassmann I think what is now of interesting new research line is to search for additional autoantibodies in the population of multiple sclerosis patients. There are indications from pathology that there are certainly more patients who may have pathogenic autoantibodies, in comparison to those patients which now can be identified as NMO or mock-autoantibody-associated disease. There is a relatively recent study suggesting that another channel, a potassium channel on oligodendrocytes and astrocytes, the KIR4.1 channel, may also be a target for pathogenic autoantibodies in multiple sclerosis. Here, however, we are still in the very early stage because the test systems are not yet fully reproducible. And we will see in the future whether this antibody association with the KIR4.1 antibody really holds true in MS patients. And if that’s the case, what patients are they and whether they differ in any way in their clinical presentation or also response to therapy.   MSDF Is there a way to survey patients and essentially see what commonalities they have in antibody reactivity, and zero in on it that way, looking at a wide array of antibodies in various patients and seeing if they have reactivities in common?   Dr. Lassmann I think this is valid as a second step. But there is another alternative strategy which is now very well established also for other diseases, including paraneoplastic diseases or other autoimmune diseases. In that case, one can actually take the sera of the patients, and there are now new technologies developed where you can put these sera, for instance, on brain sections – normal brain sections – of either humans or animals and test whether they bind to specific structures.    This has been tried for nearly 30 years now, but only recently, new technologies became available which make that in a much more specific way. And this has been very successful in identifying new diseases which are associated with antibodies against a variety of neurotransmitter receptors or ion channels. So they certainly, in general, have not the spectrum of multiple sclerosis. They may have epilepsy. They may have psychosis. They may have motor neuron diseases, other things. But, on the other hand, the same technique can also be used to identify in multiple sclerosis patients whether some of them have actually antibodies which bind to brain tissue. And when that is established, one can actually then isolate the specific protein with the antibodies out of the brain tissue, and then, with modern molecular biology technology, can identify the antigen.   This is a strategy which has very nicely and very successfully shown for other diseases. And this was also, in principle, the strategy how people found evidence for these, for instance, KIR4.1 antibodies and also for the NMO antibodies.   MSDF Finally, do you envision being able to develop specific treatments if you find out specific autoantibodies or causes of some of these conditions?   Dr. Lassmann It may very well be. I think there are two dimensions on that. The one dimension is that such patients have pathogenic autoantibodies, and that certainly will have implications for therapy. That means that you will try to block the pathogenic action of the antibodies in general. In that case, it doesn’t make a difference whether the antibody is now directed against a neuron or against an astrocyte or against an oligodendrocyte. And this is a strategy which is actually now already approached in many different conditions, and neuromyelitis optica certainly is a disease where this is relatively advanced in this respect.   Now, the other possibility would be to try to find therapies which are then counteracting specifically the destruction of the particular cells which contain the antigen. So it can very well be that, for instance, an antibody against a neurotransmitter receptor will have a different implication on neuronal function, in comparison to an antibody against an astrocyte or an oligodendrocyte. Here, if these are just blocking antibodies and not antibodies which destroy the tissue, one can actually then try also symptomatic therapies with interfering with these channels directly.   MSDF Is there any thought towards trying to induce tolerance or clonal deletion of the pathogenic clones?   Dr. Lassmann This is obviously the dream of immunologists, and it would be extremely attractive. And it works extremely well in inbred mouse models with a very well-defined disease induction process. The strategy is very dangerous in a genetically heterogeneous population and also in a disease process which may be induced by different mechanisms. So, in that case, the big danger is that this tolerizing strategy in certain patients, for instance, with a certain histocompatibility genetics, actually is counterproductive and increases the immune response. And this is actually a problem which is very, very difficult to solve, in the aim of translating this mouse data into humans.   [transition music]   Thank you for listening to Episode Forty-six of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the 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]

Hello, and welcome to Episode Forty-Six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller. This week’s podcast features the first part of a two-part interview with Dr. Hans Lassmann, who discusses biomarkers in multiple sclerosis. But first, here are some of the new items in the MS Discovery Forum. According to our curated list of the latest scientific articles related to MS, 61 such articles were published last week. To see the list, go to <a href="http://msdiscovery.org" rel="nofollow" target="_blank">msdiscovery.org</a> and click on Papers. We selected two of those papers as Editors’ Picks. One, on the prevalence of pain in MS, found that around two-thirds of MS patients experience pain, and this symptom is associated with disability, depression, and especially anxiety. The other editor’s pick is a study of a toxin produced by Clostridium perfringens, a common bacterium often found in the gut that produces an MS-like disease in sheep. This epsilon toxin selectively kills oligodendrocytes while preserving all other neural elements. Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week we added 2 new trials and 5 other pieces of information. The drugs with important additions are dalfampridine, dimethyl fumarate, and fingolimod. To find information on all 44 compounds, visit <a href="http://msdiscovery.org" rel="nofollow" target="_blank">msdiscovery.org</a> and click first on Research Resources and then on Drug-Development Pipeline [transition music] Now to the interview. Dr. Hans Lassmann of the Medical University of Vienna in Austria, is one of the most prolific and highly respected MS researchers in the world. In this first part of a two part interview, Dr. Lassmann discusses biomarkers in MS and related conditions such as neuromyelitis optica and how the two conditions may differ important for therapy. Interviewer – Dan Keller Let’s talk about new markers in MS or differentiating conditions from MS. What’s coming along, and what do we know now? Interviewee – Hans Lassmann Well, there has been a very important development during the last years. And this was the technical development of assays which can really identify pathogenic autoantibodies which can modify the inflammatory process in the central nervous system. The major trick behind was that these assays are, in essence, based on cells which are transfected with the respective antigen, and so they express the respective antigen on the surface of the cell. And one can now identify those autoantibodies which really bind to the surface of the cell and are pathogenic, in comparison to those antibodies which recognize epitopes, for instance, within the cells, which cannot be reached by the antibodies in the in vivo situation, and which, therefore, are not pathogenic. MSDF Can you give me some examples of these kinds of antibodies? Dr. Lassmann So the first antibody which was the antibody against aquaporin 4, which has been shown to be associated with neuromyelitis optica, at least with a large fraction of patients with neuromyelitis optica. And this antibody then was very well characterized, and it turned out that it is directed against aquaporin 4, which is a water channel in astrocytes. And when patients have these antibodies on the background of an inflammatory disease in the central nervous system, these antibodies can reach their astrocytic targets and destroy the astrocytes, which then leads to secondary demyelination and neurodegeneration. Having these antibodies, it was then possible to define the clinical spectrum of the disease, and it turned out that it is very strictly associated with neuromyelitis optica, but that the spectrum of the disease is broader than only affecting the spinal cord and the optic nerve. So these patients actually have also lesions in other regions of the brain. But they are still different from those lesions which you see multiple sclerosis. It was then also possible to define the clinical spectrum of the disease. And, again, differences to multiple sclerosis became very clear. And, finally, it was also possible to then look in these patients with these aquaporin 4 antibodies how they respond to the current treatment strategies which have been established for multiple sclerosis. And it turned out that several of the key therapies for multiple sclerosis, including interferons but also natalizumab or fingolimod, can actually make the disease worse in patients with neuromyelitis optica. So that was the first example that a disease which has originally been defined as a disease in the spectrum of multiple sclerosis has emerged as a separate and distinguishable disease which requires also different treatment in the patients. MSDF It seems like neuromyelitis optica has components of autoimmune disease. So why do these compounds that work in MS potentially make the condition worse in NMO? Dr. Lassmann This is currently not yet clear. One possibility is that the action of pathogenic antibodies makes the difference. The immune mechanisms are certainly different in a purely T-cell mediated disease, in comparison to disease which is mediated by a combination of T-cells and antibodies. And that could possibly explain why differences are seen. There is another possibility is that some of these drugs actually stimulate the B-cell response or increase the B-cell response in the peripheral blood, and with that possibly also the antibody response. So, in that case, the T-cell mediated inflammation would be suppressed, but the antibody-mediated effects would be enhanced. And that could certainly also play a role. But these are, at the present moment, not proven. MSDF But even in MS there’s evidence for B-cell trafficking and B-cell participation, but it seems to be less important or am I off base? Dr. Lassmann No, this is a very interesting question. There is clearly a B-cell component in multiple sclerosis, and it has also been shown that depleting B-cells, for instance, with an antibody against CD20 can actually have a very good therapeutic effect in multiple sclerosis. However, we have to keep in mind that B-cells not only produce antibodies, but they have also other immunological functions. So one function, for instance, is that they help the T-cells, for instance, by very efficient antigen presentation. So by eliminating B-cells, you get also a decrease of the T-cell response. But this is not only one possibility. There are other possibilities that B-lymphocytes actually can also produce cytokines – proinflammatory cytokines – which may directly act on the tissue and damage the tissue independent from antibodies. MSDF Getting back to NMO, if someone tests negative for antibody, but has clinical signs, does that rule out NMO or are you just not detecting antibodies or is it always required or not? Dr. Lassmann So it rules out an aquaporin 4 antibody associated form of NMO, but a fraction of NMO patients – it’s around between 10 and 20% – which have a clinical presentation of NMO, but have no antibodies against aquaporin 4. There is currently very much effort to define what is the mechanism in these patients. And it turned out that a fraction of these aquaporin 4 antibody-negative NMO patients actually have antibodies against myelin oligodendrocyte glycoprotein. And this leads, actually now, to a second type of disease which can be separated from multiple sclerosis. These are patients with high titers of pathogenic antibodies against myelin oligodendrocyte glycoprotein. Now, again, these patients, when you look at them at pathology, you would clearly define the disease as multiple sclerosis because they have inflammation, and they have very selective primary demyelination. And this is different from what you see in NMO where the astrocyte pathology is the earliest event. But in those patients with the MOG antibodies, its demyelination sort of hallmark, actually, of multiple sclerosis…of the disease process in multiple sclerosis. However, when you now analyze these patients with mock antibodies, clinically you see that the clinical presentation is different from the classical presentation of multiple sclerosis patients. These antibodies are, for instance, frequent in children with inflammatory demyelinating disease of a spectrum of acute disseminated encephalomyelitis or relapsing disseminated encephalomyelitis or even patients with a disease similar to relapsing, remitting multiple sclerosis. This is in children. In adults, you find these antibodies in a fraction of NMO patients. But there are also other patients who have a disease which is more similar to what is seen in multiple sclerosis, with the exception that they have relatively large and aggressive lesions, and also that they have, relatively frequently, lesions in the brain stem such as, for instance, the pons or the medulla oblongata. And, again, it seems to be that here a new disease entity appears which can be separated from multiple sclerosis. Regarding therapy of these patients, we don’t have yet the data which we need to have. It can be speculated that the therapeutic response may possibly be more similar to those patients with NMO in comparison to the classical MS patients, but to know that we would have to have much larger cohorts of patients who have been treated with the different regimes. MSDF Do some of these do worse on the typical MS treatments such as natalizumab or fingolimod? Dr. Lassmann These data currently are not yet existing. It’s also because, due to these possible problems related to NMO, generally now, patients with mock-antibody-associated diseases are more likely to be treated with global immunosuppression or with rituximab, so the anti-CD20 antibody. And clinicians are very reluctant to use these therapies which have been shown to make disease worse in NMO in these mock patients. So we don’t have the data, currently. MSDF Are there separate etiologies, does it look like here, the MOG versus classical MS? Dr. Lassmann This comes to the important question about the etiology of MS in general. We have to admit that we don’t know what is the real etiology of multiple sclerosis. It is thought to be an autoimmune disease, but this is not finally proven. It may also be associated with infections – Epstein-Barr virus infection is, for instance, one possible example. And there are certainly other theories also, which discuss completely different mechanisms of disease pathogenesis in multiple sclerosis. It is clearly that all these diseases, including NMO, mock antibody associated disease, and MS are chronic inflammatory diseases. But what drives the inflammation is currently not yet known. MSDF Is it possible there’s an initial insult to oligodendrocytes which then sort of precipitate a chain reaction cascade? Dr. Lassmann This is also one of the theories which is put forward, but one has to say that with a bit caution, because there are experimental models where you can actually destroy oligodendrocytes in the central nervous system which do not lead to an autoimmune disease which is somehow related or similar to multiple sclerosis. MSDF Anything interesting or important to add on the subject, in this context? Dr. Lassmann I think what is now of interesting new research line is to search for additional autoantibodies in the population of multiple sclerosis patients. There are indications from pathology that there are certainly more patients who may have pathogenic autoantibodies, in comparison to those patients which now can be identified as NMO or mock-autoantibody-associated disease. There is a relatively recent study suggesting that another channel, a potassium channel on oligodendrocytes and astrocytes, the KIR4.1 channel, may also be a target for pathogenic autoantibodies in multiple sclerosis. Here, however, we are still in the very early stage because the test systems are not yet fully reproducible. And we will see in the future whether this antibody association with the KIR4.1 antibody really holds true in MS patients. And if that’s the case, what patients are they and whether they differ in any way in their clinical presentation or also response to therapy. MSDF Is there a way to survey patients and essentially see what commonalities they have in antibody reactivity, and zero in on it that way, looking at a wide array of antibodies in various patients and seeing if they have reactivities in common? Dr. Lassmann I think this is valid as a second step. But there is another alternative strategy which is now very well established also for other diseases, including paraneoplastic diseases or other autoimmune diseases. In that case, one can actually take the sera of the patients, and there are now new technologies developed where you can put these sera, for instance, on brain sections – normal brain sections – of either humans or animals and test whether they bind to specific structures. This has been tried for nearly 30 years now, but only recently, new technologies became available which make that in a much more specific way. And this has been very successful in identifying new diseases which are associated with antibodies against a variety of neurotransmitter receptors or ion channels. So they certainly, in general, have not the spectrum of multiple sclerosis. They may have epilepsy. They may have psychosis. They may have motor neuron diseases, other things. But, on the other hand, the same technique can also be used to identify in multiple sclerosis patients whether some of them have actually antibodies which bind to brain tissue. And when that is established, one can actually then isolate the specific protein with the antibodies out of the brain tissue, and then, with modern molecular biology technology, can identify the antigen. This is a strategy which has very nicely and very successfully shown for other diseases. And this was also, in principle, the strategy how people found evidence for these, for instance, KIR4.1 antibodies and also for the NMO antibodies. MSDF Finally, do you envision being able to develop specific treatments if you find out specific autoantibodies or causes of some of these conditions? Dr. Lassmann It may very well be. I think there are two dimensions on that. The one dimension is that such patients have pathogenic autoantibodies, and that certainly will have implications for therapy. That means that you will try to block the pathogenic action of the antibodies in general. In that case, it doesn’t make a difference whether the antibody is now directed against a neuron or against an astrocyte or against an oligodendrocyte. And this is a strategy which is actually now already approached in many different conditions, and neuromyelitis optica certainly is a disease where this is relatively advanced in this respect. Now, the other possibility would be to try to find therapies which are then counteracting specifically the destruction of the particular cells which contain the antigen. So it can very well be that, for instance, an antibody against a neurotransmitter receptor will have a different implication on neuronal function, in comparison to an antibody against an astrocyte or an oligodendrocyte. Here, if these are just blocking antibodies and not antibodies which destroy the tissue, one can actually then try also symptomatic therapies with interfering with these channels directly. MSDF Is there any thought towards trying to induce tolerance or clonal deletion of the pathogenic clones? Dr. Lassmann This is obviously the dream of immunologists, and it would be extremely attractive. And it works extremely well in inbred mouse models with a very well-defined disease induction process. The strategy is very dangerous in a genetically heterogeneous population and also in a disease process which may be induced by different mechanisms. So, in that case, the big danger is that this tolerizing strategy in certain patients, for instance, with a certain histocompatibility genetics, actually is counterproductive and increases the immune response. And this is actually a problem which is very, very difficult to solve, in the aim of translating this mouse data into humans. [transition music] Thank you for listening to Episode Forty-six of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. [outro music]

Multiple Sclerosis Discovery -- Episode 46 with Dr. Hans Lassmann (Part 1)

[intro music]   Host – Dan Keller  Hello, and welcome to Episode Seventeen of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Dr. Hans Lassmann about the usefulness of animal models for studying multiple sclerosis. But to begin, here’s a brief summary of the developments at the MS Discovery Forum at msdiscovery.org.   In the progressive stage of multiple sclerosis, some astrocytes appear to upregulate genes that intensify inflammation and neurodegeneration. Researchers think that genetic changes cause astrocytes to release a fatty molecule that beckons inflammatory monocytes from the blood into the brain. A drug, miglustat, currently used in the treatment of Gaucher’s disease, may be a good candidate to repurpose as a drug to inhibit astrocytes from initiating this destructive process.   The so-called “long life” protein, Klotho, may hold the keys to remyelination. Named after the Greek goddess responsible for “spinning the thread of life,” an abundance of Klotho leads to longer lifespans in mice. The protein has also been associated with numerous age-related conditions such as Alzheimer’s disease. Recent research noted that reduced Klotho was associated with myelin degeneration in normal, aging Rhesus monkeys. A small molecule, currently known as ‘Compound A’ can promote Klotho in the CNS of mice, enhancing remyelination in the cuprizone mouse model.   We recently released a new data visualization comparing various characteristics – such as age, gender, and EDSS scores – across 74 clinical trials. You can look at each characteristic in every trial, or compare the means of all the trials. To view, go to the “research resources” tab at msdiscovery.org and click on “data visualizations.” Then click on “RRMS and CIS – Baseline Characteristics.”   [transition music]   Now to the interview. Dr. Hans Lassmann studies the pathogenesis of inflammatory diseases at the Center for Brain Research at the Medical University of Vienna in Austria. He met with MSDF at the MS Boston meeting in September to discuss demyelinating disorders.   Interviewer – Dan Keller In terms of what we can learn from other demyelinating diseases, ones caused by infectious agents, how can this shed light on the processes and possible treatment of MS?   Interviewee – Hans Lassmann That depends, obviously, on the models which we are looking. I think there is a major difference between multiple sclerosis and these other experimental models, because the experimental models which really induce large areas of demyelination always are associated with infection of oligodendrocytes. But in multiple sclerosis, there is actually no indication that oligodendrocytes are infected. Now this has consequences that also the demyelination is different in these experimental models because it follows the death of single infected oligodendrocytes. That means that lesions have, more or less, some sort of moth-eaten edges where single oligodendrocytes are falling apart with small pieces of demyelination in between intact myelin, whereas in multiple sclerosis the demyelination is a sharply demarcated lesion which does not follow the oligodendrocyte territories. What we, however, can learn from the models is the question how the brain handles an infectious process in the white matter with respect to inflammation and the amplification mechanisms of tissue injury in the demyelinating process.    MSDF So are they similar enough that we can discern something useful from it, even though the patterns do seem to differ in some ways?   Dr. Lassmann Yes, we can. For instance, there is a major difference between the autoimmune models which we have and the virus models. The autoimmune models are predominantly mediated, or driven, by an MHC class 2 CD4-positive T cell response, whereas the virus models are predominantly driven by a CD8 T cell response. Interestingly, in multiple sclerosis, also the CD8 T cell response dominates. So we can actually learn a lot from these models on the mechanisms of CD8-mediated inflammation in the brain, and also on what are the consequences of a CD8-mediated inflammation in the brain with respect to tissue injury.    MSDF What about some of the diseases that are closely associated with MS but are distinct from it, like neuromyelitis optica and, I guess, concentric sclerosis and others, how do they shed light on things, if they do?   Dr. Lassmann I think they shed a lot of lights on that. Let’s take first neuromyelitis optica. Here we are in a very favored situation because we know it is an autoimmune disease and we know the specific target antigen, and the specific target antigen is a water channel in astrocytes. So from that we have actually learned how antibodies against these astrocytes actually induce the tissue injury, in that case, by first destroying the astrocytes themselves, and then secondarily leading to oligodendrocyte destruction and demyelination, and also some axonal loss. So that actually is a perfect model for a scenario where T cells and pathogenic antibodies play a role in disease mechanisms, and that is apparently also the case in a subset of multiple sclerosis patients, but only in a subset.    MSDF How does the glia enter into this, both as a target and maybe as a mediator or effector?   Dr. Lassmann Now, obviously, the prime target in multiple sclerosis is the oligodendrocyte and the myelin sheath, but there is obviously also pathology in other glial cells. There is an astrocytic pathology, and there is also a microglia activation and pathology in these cases. Now, the astrocytic pathology itself may also contribute to the lesion propagation because when astrocytes are also destroyed in the lesion, or primarily destroyed in the lesion, it will also secondarily lead to the oligodendrocyte loss and demyelination. This is a classical example of neuromyelitis optica.    MSDF Is that through mechanisms of macrophage activation, or debris, or mediator release, or toxic release?   Dr. Lassmann No. From the astrocyte pathology, it’s so that the astrocytes and the oligodendrocytes are connected with gap junctions, and the astrocytes play a major role in supporting the energy demand of oligodendrocytes. So if you kill out the astrocytes, the oligodendrocytes starve to death.   MSDF Now that you bring up energy, can we learn anything from mitochondrial diseases and their consequences?   Dr. Lassmann Yes, here we can learn a lot because the mitochondrial injury and damage is in the center of neurodegeneration and demyelination in multiple sclerosis. In that case, in the disease the mitochondrial injury is apparently driven and induced by oxidative injury, but that it leads in a secondary consequence also to mitochondrial gene deletion, so to deletions of mitochondrially-encoded genes. And here the mitochondrially-encoded gene deletions are also present in many mitochondrial diseases, and for that, obviously, mitochondrial diseases are perfect models to study these aspects of multiple sclerosis pathogenesis. A key issue, for instance, is the mechanisms of mitochondrial quality control. Normally, it’s so that the damaged mitochondrion is just removed from the cell in autophagosomes. But this needs very specific mechanisms of recognition. If this quality control is actually missing or disturbed, then these damaged mitochondria can expand, can clonally expand, and then you get an upward cells having more and more and more damaged mitochondria. And that’s, for instance, also a mechanism which is very prominent in mitochondrial diseases.    MSDF Is that a failure of phagosomes? Is there a defect at that level?   Dr. Lassmann No, I think it’s rather a defect in the mitochondrial proteins, because the mitochondrial proteins are expressed on the surface indicating the phagocytic system, whether they are intact or damaged. And when this process is more or less disturbed, then the phagosomes don’t recognize the damaged mitochondria anymore.    MSDF What are you doing now? What sort of paths are you pursuing in terms of these things that we’ve been discussing?    Dr. Lassmann We have in principles three major projects. The first is that we try to define more precisely what is the nature of the inflammatory response in multiple sclerosis and in to what extent this is different from what is seen in the respective experimental autoimmune models. Now, the second project deals with mechanisms of demyelination, and here the key question is there is soluble demyelinating factor in multiple sclerosis, but it’s not very clear what exactly the soluble factor is; it could be demyelinating antibodies, and that can be modeled in experimental models, like autoimmune encephalitis. But many data suggests that there must be other factors which are not immunoglobulin and not antibodies which are responsible for this demyelination. And then the third project deals with the progressive stage of multiple sclerosis, and here it’s the central pathogenic pathways, oxidative injury and mitochondrial injury. And our projects now go in the direction of what is the course of this massive oxidative damage in multiple sclerosis, how does that relate to mitochondrial injury, and what is the consequences then on the tissue with respect to energy deficiency and other things.    MSDF In progressive disease, do you see a shift towards more mitochondrial damage and oxidative damage or stress?   Dr. Lassmann We have oxidative damage already in the early stages of MS, but in the early stages of MS the oxidative injury seems to be mainly driven by the inflammatory component; that means by inflammation, activation of microglia and then the production of reactive oxygen-producing enzymes. In the progressive stage of MS, we get additional amplification factors for oxidative injury, and they are related to brain aging and related to accumulation of lesion burden. So what we get, on the one hand, an age-related increase of iron in the human brain, and iron can massively potentiate oxidative injury by a reaction which is the so-called Fenton reaction. The second thing is that you have accumulated tissue injury in multiple sclerosis with retrograde and anterograde degeneration, and that leads to progressive microglia activation, which then can actually be transformed more easily in cytotoxic microglia cells by additional proinflammatory stimuli. And the third mechanism is that the mitochondrial injury increases, and in particular the mitochondrial gene deletion and the clonal expansion of defective mitochondria expand in the progressive stage with disease duration. And mitochondria, when they are damaged, they can liberate electrons, and the electrons can actually, again, react with oxygen, producing a reactive oxygen species. And so this is a more or less self-amplifying process which then leads to enhancement of neurodegeneration and demyelination.    MSDF Is there a role for glutathione here?   Dr. Lassmann Yes. Glutathione is one of the key molecules for the oxidative injury, and obviously this is one of the players, but it’s only one.    MSDF It’s a player in the injury or in limiting injury?   Dr. Lassmann That is not entirely clear yet.   MSDF What have we missed or you think is important to discuss or add?   Dr. Lassmann There is certainly in the multiple sclerosis therapy also the tests to increase remyelination and possible regeneration in the lesions, including stem cell therapies or increasing remyelination by soluble factors by cytokines and growth factors. This is all very interesting, but the key point is that as long as the disease process is active, newly-formed myelin is destroyed relatively quickly.    MSDF It seems that there’s almost an analogy to osteoporosis where it’s a balance between formation and destruction. Is there ongoing remyelination or turnover in the healthy brain?   Dr. Lassmann Yes, there is a myelin turnover in the healthy brain, but there is also a profound attempt for remyelination in multiple sclerosis lesions. And what you see even in the early stages in very active MS lesions, you always find signs of ongoing remyelination. But, interestingly, in these early stages, really established remyelination is generally missing, and we have performed a study on that issue showing that if you have disease activity, the remyelinated areas are actually more prone to show new demyelination compared to the normal old myelin which is in there. So that suggests that this remyelination is present and all attempts are present, but this process is relatively instable as long as the disease process is active.   MSDF Is there a thought of being able to inhibit that further, or accelerate a destructive process in these remyelinated areas?   Dr. Lassmann I think this is not really specific for the remyelinated areas. If we are a [?], for instance, that disease process or the progression of the tissue damage can be stopped, for instance, with measurements making some sort of mitochondrial protection, or with certain antioxidative therapeutic strategies, then it will certainly be beneficial both for the old lesions and the newly formed lesions and the remyelinated lesions. But that’s more or less something which has to be solved before we can think of really effective remyelinating strategy.   [transition music]   Thank you for listening to Episode Seventeen of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.    Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.   [outro music] 

[intro music] Host – Dan Keller  Hello, and welcome to Episode Seventeen of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller. This week’s podcast features an interview with Dr. Hans Lassmann about the usefulness of animal models for studying multiple sclerosis. But to begin, here’s a brief summary of the developments at the MS Discovery Forum at <a href="http://msdiscovery.org" rel="nofollow" target="_blank">msdiscovery.org</a>. In the progressive stage of multiple sclerosis, some astrocytes appear to upregulate genes that intensify inflammation and neurodegeneration. Researchers think that genetic changes cause astrocytes to release a fatty molecule that beckons inflammatory monocytes from the blood into the brain. A drug, miglustat, currently used in the treatment of Gaucher’s disease, may be a good candidate to repurpose as a drug to inhibit astrocytes from initiating this destructive process. The so-called “long life” protein, Klotho, may hold the keys to remyelination. Named after the Greek goddess responsible for “spinning the thread of life,” an abundance of Klotho leads to longer lifespans in mice. The protein has also been associated with numerous age-related conditions such as Alzheimer’s disease. Recent research noted that reduced Klotho was associated with myelin degeneration in normal, aging Rhesus monkeys. A small molecule, currently known as ‘Compound A’ can promote Klotho in the CNS of mice, enhancing remyelination in the cuprizone mouse model. We recently released a new data visualization comparing various characteristics – such as age, gender, and EDSS scores – across 74 clinical trials. You can look at each characteristic in every trial, or compare the means of all the trials. To view, go to the “research resources” tab at <a href="http://msdiscovery.org" rel="nofollow" target="_blank">msdiscovery.org</a> and click on “data visualizations.” Then click on “RRMS and CIS – Baseline Characteristics.” [transition music] Now to the interview. Dr. Hans Lassmann studies the pathogenesis of inflammatory diseases at the Center for Brain Research at the Medical University of Vienna in Austria. He met with MSDF at the MS Boston meeting in September to discuss demyelinating disorders. Interviewer – Dan Keller In terms of what we can learn from other demyelinating diseases, ones caused by infectious agents, how can this shed light on the processes and possible treatment of MS? Interviewee – Hans Lassmann That depends, obviously, on the models which we are looking. I think there is a major difference between multiple sclerosis and these other experimental models, because the experimental models which really induce large areas of demyelination always are associated with infection of oligodendrocytes. But in multiple sclerosis, there is actually no indication that oligodendrocytes are infected. Now this has consequences that also the demyelination is different in these experimental models because it follows the death of single infected oligodendrocytes. That means that lesions have, more or less, some sort of moth-eaten edges where single oligodendrocytes are falling apart with small pieces of demyelination in between intact myelin, whereas in multiple sclerosis the demyelination is a sharply demarcated lesion which does not follow the oligodendrocyte territories. What we, however, can learn from the models is the question how the brain handles an infectious process in the white matter with respect to inflammation and the amplification mechanisms of tissue injury in the demyelinating process.  MSDF So are they similar enough that we can discern something useful from it, even though the patterns do seem to differ in some ways? Dr. Lassmann Yes, we can. For instance, there is a major difference between the autoimmune models which we have and the virus models. The autoimmune models are predominantly mediated, or driven, by an MHC class 2 CD4-positive T cell response, whereas the virus models are predominantly driven by a CD8 T cell response. Interestingly, in multiple sclerosis, also the CD8 T cell response dominates. So we can actually learn a lot from these models on the mechanisms of CD8-mediated inflammation in the brain, and also on what are the consequences of a CD8-mediated inflammation in the brain with respect to tissue injury.  MSDF What about some of the diseases that are closely associated with MS but are distinct from it, like neuromyelitis optica and, I guess, concentric sclerosis and others, how do they shed light on things, if they do? Dr. Lassmann I think they shed a lot of lights on that. Let’s take first neuromyelitis optica. Here we are in a very favored situation because we know it is an autoimmune disease and we know the specific target antigen, and the specific target antigen is a water channel in astrocytes. So from that we have actually learned how antibodies against these astrocytes actually induce the tissue injury, in that case, by first destroying the astrocytes themselves, and then secondarily leading to oligodendrocyte destruction and demyelination, and also some axonal loss. So that actually is a perfect model for a scenario where T cells and pathogenic antibodies play a role in disease mechanisms, and that is apparently also the case in a subset of multiple sclerosis patients, but only in a subset.  MSDF How does the glia enter into this, both as a target and maybe as a mediator or effector? Dr. Lassmann Now, obviously, the prime target in multiple sclerosis is the oligodendrocyte and the myelin sheath, but there is obviously also pathology in other glial cells. There is an astrocytic pathology, and there is also a microglia activation and pathology in these cases. Now, the astrocytic pathology itself may also contribute to the lesion propagation because when astrocytes are also destroyed in the lesion, or primarily destroyed in the lesion, it will also secondarily lead to the oligodendrocyte loss and demyelination. This is a classical example of neuromyelitis optica.  MSDF Is that through mechanisms of macrophage activation, or debris, or mediator release, or toxic release? Dr. Lassmann No. From the astrocyte pathology, it’s so that the astrocytes and the oligodendrocytes are connected with gap junctions, and the astrocytes play a major role in supporting the energy demand of oligodendrocytes. So if you kill out the astrocytes, the oligodendrocytes starve to death. MSDF Now that you bring up energy, can we learn anything from mitochondrial diseases and their consequences? Dr. Lassmann Yes, here we can learn a lot because the mitochondrial injury and damage is in the center of neurodegeneration and demyelination in multiple sclerosis. In that case, in the disease the mitochondrial injury is apparently driven and induced by oxidative injury, but that it leads in a secondary consequence also to mitochondrial gene deletion, so to deletions of mitochondrially-encoded genes. And here the mitochondrially-encoded gene deletions are also present in many mitochondrial diseases, and for that, obviously, mitochondrial diseases are perfect models to study these aspects of multiple sclerosis pathogenesis. A key issue, for instance, is the mechanisms of mitochondrial quality control. Normally, it’s so that the damaged mitochondrion is just removed from the cell in autophagosomes. But this needs very specific mechanisms of recognition. If this quality control is actually missing or disturbed, then these damaged mitochondria can expand, can clonally expand, and then you get an upward cells having more and more and more damaged mitochondria. And that’s, for instance, also a mechanism which is very prominent in mitochondrial diseases.  MSDF Is that a failure of phagosomes? Is there a defect at that level? Dr. Lassmann No, I think it’s rather a defect in the mitochondrial proteins, because the mitochondrial proteins are expressed on the surface indicating the phagocytic system, whether they are intact or damaged. And when this process is more or less disturbed, then the phagosomes don’t recognize the damaged mitochondria anymore.  MSDF What are you doing now? What sort of paths are you pursuing in terms of these things that we’ve been discussing?  Dr. Lassmann We have in principles three major projects. The first is that we try to define more precisely what is the nature of the inflammatory response in multiple sclerosis and in to what extent this is different from what is seen in the respective experimental autoimmune models. Now, the second project deals with mechanisms of demyelination, and here the key question is there is soluble demyelinating factor in multiple sclerosis, but it’s not very clear what exactly the soluble factor is; it could be demyelinating antibodies, and that can be modeled in experimental models, like autoimmune encephalitis. But many data suggests that there must be other factors which are not immunoglobulin and not antibodies which are responsible for this demyelination. And then the third project deals with the progressive stage of multiple sclerosis, and here it’s the central pathogenic pathways, oxidative injury and mitochondrial injury. And our projects now go in the direction of what is the course of this massive oxidative damage in multiple sclerosis, how does that relate to mitochondrial injury, and what is the consequences then on the tissue with respect to energy deficiency and other things.  MSDF In progressive disease, do you see a shift towards more mitochondrial damage and oxidative damage or stress? Dr. Lassmann We have oxidative damage already in the early stages of MS, but in the early stages of MS the oxidative injury seems to be mainly driven by the inflammatory component; that means by inflammation, activation of microglia and then the production of reactive oxygen-producing enzymes. In the progressive stage of MS, we get additional amplification factors for oxidative injury, and they are related to brain aging and related to accumulation of lesion burden. So what we get, on the one hand, an age-related increase of iron in the human brain, and iron can massively potentiate oxidative injury by a reaction which is the so-called Fenton reaction. The second thing is that you have accumulated tissue injury in multiple sclerosis with retrograde and anterograde degeneration, and that leads to progressive microglia activation, which then can actually be transformed more easily in cytotoxic microglia cells by additional proinflammatory stimuli. And the third mechanism is that the mitochondrial injury increases, and in particular the mitochondrial gene deletion and the clonal expansion of defective mitochondria expand in the progressive stage with disease duration. And mitochondria, when they are damaged, they can liberate electrons, and the electrons can actually, again, react with oxygen, producing a reactive oxygen species. And so this is a more or less self-amplifying process which then leads to enhancement of neurodegeneration and demyelination.  MSDF Is there a role for glutathione here? Dr. Lassmann Yes. Glutathione is one of the key molecules for the oxidative injury, and obviously this is one of the players, but it’s only one.  MSDF It’s a player in the injury or in limiting injury? Dr. Lassmann That is not entirely clear yet. MSDF What have we missed or you think is important to discuss or add? Dr. Lassmann There is certainly in the multiple sclerosis therapy also the tests to increase remyelination and possible regeneration in the lesions, including stem cell therapies or increasing remyelination by soluble factors by cytokines and growth factors. This is all very interesting, but the key point is that as long as the disease process is active, newly-formed myelin is destroyed relatively quickly.  MSDF It seems that there’s almost an analogy to osteoporosis where it’s a balance between formation and destruction. Is there ongoing remyelination or turnover in the healthy brain? Dr. Lassmann Yes, there is a myelin turnover in the healthy brain, but there is also a profound attempt for remyelination in multiple sclerosis lesions. And what you see even in the early stages in very active MS lesions, you always find signs of ongoing remyelination. But, interestingly, in these early stages, really established remyelination is generally missing, and we have performed a study on that issue showing that if you have disease activity, the remyelinated areas are actually more prone to show new demyelination compared to the normal old myelin which is in there. So that suggests that this remyelination is present and all attempts are present, but this process is relatively instable as long as the disease process is active. MSDF Is there a thought of being able to inhibit that further, or accelerate a destructive process in these remyelinated areas? Dr. Lassmann I think this is not really specific for the remyelinated areas. If we are a [?], for instance, that disease process or the progression of the tissue damage can be stopped, for instance, with measurements making some sort of mitochondrial protection, or with certain antioxidative therapeutic strategies, then it will certainly be beneficial both for the old lesions and the newly formed lesions and the remyelinated lesions. But that’s more or less something which has to be solved before we can think of really effective remyelinating strategy. [transition music] Thank you for listening to Episode Seventeen of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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.  <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. 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