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Hello, and welcome to Episode Eighteen of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.
This week’s podcast features an interview with Dr. Samuel Ludwin about new approaches to remyelinating therapies. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.
The term “neuroscience” makes it very clear who is the star of the show—neurons. But over the past few years, glial cells have been elbowing their way in from supporting cast to stars in their own right. We recently reported a story about how oligodendrocytes need to make new myelin in order for mice to learn a new motor task effectively. The study demonstrated how glia are required in active learning, as well as highlighted the importance of targeting remyelination in new therapies for demyelinating disorders.
Speaking of remyelination, we recently published an article in our animal model section about zebrafish and their use in studying MS. Though a fish might not jump to mind as an adequate model for modeling the complexities of a disease like MS, zebrafish are actually very useful for studying myelination. Researchers can engineer the fish to be transparent while also fluorescently tagging myelin, oligodendrocytes, and more. If you’re curious to learn more, go to the “Animal Models” section under “Research Resources” and click on “Zebrafish.”
Finally, we recently added a new data visualization examining the differences in baseline characteristics of patients in 74 RRMS and CIS clinical trials. You can easily see how individual trials compare to the overall mean values of gender, age, Expanded Disability Status Scale score, the number of gadolinium enhancing lesions, and the volume of T2 lesions. To see the new data visualization, click on the “Data Visualizations” tab under “Research Resources,” and then click on “RRMS and CIS baseline characteristics.”
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Now to the interview. Dr. Samuel Ludwin is a neuropathologist who is currently a visiting scientist at the Montreal Neurological Institute. He met with MSDF to talk about the latest in remyelination therapies.
Interviewer—Dan Keller
In terms of remyelination, what do we know now? Are there new thoughts about mechanisms and are there any compounds in development that would facilitate it?
Interviewee—Samuel Ludwin
Remyelination is a very interesting process. We know that it occurs in animals. We can well demonstrate its temporal progression. We can demonstrate the conditions under which it occurs. Demonstrating this in the human is very much more complicated because we are always taking snapshots in time in looking at human specimens and we can never be sure whether we are looking at a remyelination of a previously completely demyelinated process or not. So we draw all of our analogies about human remyelination, which we believe is present in multiple sclerosis and other diseases, but we draw these analogies from what we have shown in experimental animals where we have been able to control the process.
In animals, first of all, it is very feasible for a variety of reasons. The first is that – many mammalian, especially rodent brains, and marmoset brains which we generally work on – are considered in a way functionally immature which tends to suggest that their brains are much more capable of plasticity and therefore much more able to be repaired. The same process probably does occur in humans but as I said is probably a little bit less certain. We have done a lot of work in multiple sclerosis in demonstrating that the hallmark of remyelination which is a reconstituted sheath, although with different physical characteristics to the original myelin. We can find these sheaths in the human tissue in areas that we think are remyelinating. This brings up the promise that a certain amount of natural remyelination occurs in response to demyelination in disease. There is always the hope that one can use some of the same factors that we have discovered in rodents and other experimental animals to enhance this remyelination and make for a much wider area of functional…both enhancement of function and also protection of the underlying axons.
So remyelination is one of the hopes and maybe promises in multiple sclerosis research. Proving it is a little bit more difficult. We have many possible mechanisms for enhancing remyelination. Some of them are considered to be cell-based. By that we mean what is preventing remyelination often is the destruction of the oligodendrocyte and its precursor cells which can develop into myelinating oligodendrocyte. A lack of these cells will obviously result in a deficient remyelination. Secondly, there may be blocks from either the axon which gives the message and the signal for remyelination. Thirdly, there may be physical barriers such as the reaction from other cells in response to the inflammatory insult that are hindering access by these oligodendrocytes to the axon in order to make myelin.
There are many possible reasons that we don't have adequate remyelination. For each of these, there are at least some punitive answers as to how we may enhance. There is a lot of interest in cell transplantation, especially with mesenchymal stem cells at the moment; which have been shown not only to have immunological benefits of antiinflammatory qualities but also to be able to then differentiate into these oligodendrocyte precursors which will then differentiate into myelinating oligodendrocytes. These may enable the brain to reconstitute its quotient of myelinating cells.
There are lots of attempts underway to try and prevent any of the physical barriers of access of these cells to the axon such as from the astrocytic gliosis, but there are also many drugs which have the possibility of enhancing human remyelination. Many of these have been shown to work very well in animal models. We have whole classes of drugs that enhance remyelination. There are steroidal compounds that have been shown to enhance myelination and there have been many that have been shown to either block some of the cytokines that may be hindering or interfering with the progression of oligodendrocyte maturation. Drugs that will block some of these cytokines will allow this maturation of proliferation of these cells to continue, and therefore lead to maturation. It is true to say that apart from some of the mesenchymal stem cells which have some hope; it has been very difficult to measure remyelination in response to these therapeutic attempts at the moment in humans. Certainly in rodents we have been able to do it and there are certain clinical trials going on based on some of these animal experiments. There is a trial which the NIH is doing in conjunction with the Myelin Repair Foundation over a compound 008 which has been shown to be very beneficial in certain demyelinating models and enhancing remyelination. There are certain growth factors that have been given in animals such as hepatic growth factor that have been shown to enhance the number of oligodendrocyte precursors and their development into oligodendrocytes. These all give promise for what is possible in humans but have not yet been taken to that level yet.
MSDF
It is interesting that some of the drugs are either approved for other uses or they are older drugs or derivatives of older drugs that are now resurfacing in this arena. How do some of those work?
Dr. Ludwin
What is very interesting is that there is a whole gamut of drugs that are being investigated ab intio arising out of experiments that have been shown to have an influence on the inflammatory aspect of autoimmune disease. Many of the cytokines induced by the autoimmune diseases have multiple effects on the oligodendrocyte proliferation, maturation and then access to the axon. So drugs that will inhibit this cascade of cytokines in autoimmunity will also remove some of these inhibitors and allow for enhanced proliferation and maturation and therefore enhanced remyelination. In addition, there are a whole emerging group of drugs that have been found to coincidentally have an affect experimentally on remyelination and many of these drugs have been in the pharmacopeia for other diseases and these are side effects or side discoveries. Some of them have not been used for their initial purpose for a long time and this includes a drug that is currently under clinical trials with the NIH and the Myelin Repair Foundation called MRF-008, the details of which are not public, either in mechanism or in the structure of the drug. There are also classes of drugs such as estrogen and progesterone based drugs which have been introduced because of observable influences of normal estrogen progesterone function on oligodendrocytes and Schwann cells in the periphery in culture and they relate also to hormonal variations in multiple sclerosis and are a natural outcome of some of these observations.
MSDF
It sounds like those have sort of general repair functions. I mean they are using estrogen or testing it in traumatic brain injury and things like that.
Dr. Ludwin
Oh absolutely. I mean when we look at general repair foundations, we are looking at two of them. First of all, there is the whole question of neuroprotection and second of all there is the whole question of regrowth and these in form, are we looking at regrowth of axons, sprouting of axons in multiple sclerosis. There is a large amount of axonal damage which needs to be investigated for protection and such strategies will be very useful in axonal damage and in the hope of producing axonal regeneration.
MSDF
Now I guess there is a difference between neuroprotection and remyelination. Some of these drugs do both or do they fall into separate categories?
Dr. Ludwin
Some of them may do both but in general the neuroprotective drugs are generally a different class or different kind of drugs. There is a great need to introduce them into stroke, into trauma, the neuroprotective drugs and people are looking at the same strategies that are being used for ischemia and anoxia which are the results of strokes but may also very possibly play a role in the lesions in multiple sclerosis to protect the axons. Some of these are excitotoxic protection agents which the axon is particularly susceptible to both in ischemia and in multiple sclerosis.
MSDF
You hear much more in terms of reperfusion injury, the role of excitotoxicity, particularly glutamate. Does that also enter here or is this such a chronic process that you really don't have an accumulation of glutamate?
Dr. Ludwin
No, that is a very good question. In fact, neurotransmitter excitotoxicity has been demonstrated very well in multiple sclerosis, especially in the acute lesions where perhaps most of the axonal injury takes place. We always used to think that it was all a progressive lesion but a huge amount takes place early on in and much of this is in excitotoxic damage. I might add also that in many respects the oligodendrocyte has got many of the same neurotransmitter capacities as does the axon and neuron and the oligodendrocyte itself is susceptible to excitotoxic damage as well. Excitotoxicity is a very important target for neuroprotection and protection of the oligodendrocyte as well.
MSDF
On these topics, either compounds that look promising or the process of repair itself, what have we missed, or is there anything important to add?
Dr. Ludwin
I think that covers it in general. Of course, what we really are looking for is what the triggers to the acute process are. What we are doing, the autoimmune aspect, is the largest looming figure in the one that is proven most and almost certainly represents the major way that tissue is damaged. But what provokes the autoimmune attack may give us the answer to at least preventing or slowing down the AMS process. The therapy is at the moment largely based around dampening of the autoimmune attack and preventing subsequent damage. Although I should point out that it is not only the loss of myelin that leads to excitotoxic damage in the axon but the inflammatory infiltrate that kills oligodendrocytes and myelin has the same mechanisms that kill the axon as well. We are not just trying to protect, we are trying to prevent the axon from being damaged in the first place, early.
MSDF
Very good, I appreciate it.
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Thank you for listening to Episode Eighteen of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.
Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.
We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.
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