Multiple Sclerosis Discovery -- Episode 55 with Dr. Michael Levy

[intro music] Host – Dan Keller Hello, and welcome to Episode Fifty-Five of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller. This week’s Podcast features an interview with Dr. Michael Levy, who discusses the status of regenerative stem cell therapies for multiple sclerosis. But first, here are some new items in the MS Discovery Forum. Our lead story last week looked at a way to prevent a rare but dangerous viral brain infection that can be a side effect of certain drugs. The risk of infection limits the people who can take natalizumab to prevent the inflammatory brain attacks of relapsing-remitting MS. Two new papers propose vaccinating people against the virus. Experts are still debating the underlying biology, but they say the approach should be tested in people. Every week, MSDF lists the latest scientific papers related to MS, with links to the abstracts on PubMed. Of more than 100 new studies published last week, we selected three as editor’s picks. One study comes from the Italian registry of pediatric MS patients treated with natalizumab. Researchers evaluated 101 boys and girls. Natalizumab was safe, well tolerated, and effective, they report. Time on the drug varied, but the overall mean was about three years. Most of the patients switched because of a poor response to first-line drugs, such as interferon-beta and glatiramer acetate. The patients’ sera were assessed for anti-JC virus antibodies to prevent the rare but dangerous brain infection associated with natalizumab. Two other studies caught our eye this week. One goes into the new insights from live imaging in the central nervous systems of mice. The authors outline potential applications that could lead to therapies to protect or restore myelin. Another study asked if spasticity of lower limbs could be helped with anodal transcranial direct current stimulation in 20 MS patients. The answer is no, based on the results of the small randomized double-blind clinical trial. This is not to be confused with another noninvasive technique that seems to reduce spasticity, called transcranial magnetic stimulation. Our Drug-Development Pipeline contains 44 investigational and approved agents for MS. Last week, we added an extensive meta-analysis of clinical trials, we updated information on three trials, and we added 16 other pieces of information. The drugs with important additions are alemtuzumab, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, GNbAC1, interferon beta-1a, interferon beta-1b, laquinimod, mitoxantrone, natalizumab, ocrelizumab, and teriflunomide. One update reflects the finding that ocrelizumab slows disease progression in primary progressive MS, the first drug to do so, as described in the drug-maker’s news release. Another update reflects a meta-analysis by the Cochrane Multiple Sclerosis group. It compares 39 different clinical trials involving more than 25,000 patients to rank benefits and acceptability of 15 different MS drugs. Doctors and patients need even better information to make decisions, the authors conclude. They call for more randomized studies directly comparing active agents, no more placebo-controlled studies, and long-term followup of all drug studies. The MSDF team is attending this week’s ECTRIMS meeting in Barcelona, Spain. If you, too, will be at the conference and would like to meet with us – or if you’re interested in being interviewed about your research for a future podcast – please email us at [email protected]. [transition music] And now to our interview with Dr. Michael Levy, assistant professor of neurology at Johns Hopkins University. We met in his office to talk about stem cell regenerative therapies – what the aims are and where things stand. Interviewer – Dan Keller Let's talk about regenerative stem cell therapies, but I suppose the first thing to make clear is nothing is approved yet, is that right? Interviewee – Michael Levy Nothing is even closed to being approved. There are many trials in progress in multiple sclerosis and in spinal cord injury, which is a related demyelinating condition in which stem cells are being tested, and this is worldwide, probably over 20 studies that are ongoing. MSDF What are some of the goals? Dr. Levy The goals are twofold. In multiple sclerosis in particular, the two goals are to recover function and to neuroprotect against future insults. So in spinal cord injury, for example, there's only one goal which is recovery of function, because they don't have to worry about future insults. MSDF Now no one really has the exact idea, or I guess there's many ideas, of how these would work – whether the cells would actually replace lost cells, whether there's secreted trophic factors – so are people looking at them specifically in those areas, or whatever works at this time, then they'll figure out why? Dr. Levy It certainly started off with the mechanism in mind that the cells would replace lost tissue. That was really how things started. But as they've evolved, patients have responded in part to many different types of stem cell therapies, and none of them have involved replacing lost tissue. And so there are probably many different mechanisms involved, and it's evolved into exactly what you've described, a phenomenon of wow, this really works, let's continue it and let's try to figure out what's going on in parallel. MSDF Is there also a thought that the stem cells really are just providing a supportive environment, or even a supportive structure, for natural processes to proceed if they have the right setting? Dr. Levy Oh, sure. There are some studies where the stem cells only survive, or are only around, detectable, for about one hour, and then beyond that they can't be detected, but yet they provide some significant long-lasting benefits. So exactly how they do that is not clear. MSDF Are you familiar with the mouse experiments of Jeanne Loring at Scripps; she had taken human pluripotent stem cells in a mouse model and they were gone after a week, but then the mice got up and walked around and seemed to look perfectly normal. Dr. Levy So definitely mouse models have recapitulated what we've seen in humans, which is that the stem cells provide some sort of benefit. Whether it's secretion of trophic factors, or neuroprotection or replacement of tissue, or what they call neural bridging, allowing neurons to communicate through in the alternative circuit, this is true in mice, too. So whatever is happening in humans is probably also going on in these mice. MSDF Specifically in the MS area, what are people or companies doing? Dr. Levy Specifically in MS, the most common trial that's being conducted now is testing mesenchymal stem cells--taking them from that patient, usually from the hip, purifying them in the lab, and then injecting them back into the patient, either into the bloodstream or into the spinal fluid. Initially, the goal was to try to replace lost tissue, but now the goal has evolved, and what these studies are really looking for is sort of the 6-month or 12-month outcome to see if patients recover better, have fewer relapses, and better outcomes. MSDF Now mesenchymal stem cells in themselves are not going to turn into the lost kinds of cells you really want to replace, but they do have immunomodulatory effects, is that right? Dr. Levy That's the thought. So mesenchymal stem cells are all the cells in the bone marrow that don't turn into blood cells, either red or white blood cells; it's the rest of the matrix. And in the lab, you can turn them into neuronal cells and supportive cells that you find in the brain, but that doesn't happen when you put them into spinal cord or brain; they don't tend to differentiate into neural tissue. And so they are doing something else, and part of that is probably neuromodulatory. Correct. MSDF Besides mesenchymal stem cells, people are looking at a little more differentiated cells, oligodendroglial precursor cells--you obviously want to remyelinate. Do you have an idea of what's going on with those and has there been success there? Dr. Levy So all the studies using neural stem cells and neuroglial stem cells are currently being conducted in spinal cord injury. And in spinal cord injury there is a component of demyelination, and they're hoping that those oligos migrate to that area that is demyelinated and that it will remyelinate the lesion. So all MS patients should keep an eye on those studies to see how those turn out. MSDF The difference there is you can identify an area of lesion. In the brain, you don't know exactly where lesions are going to come up, and lesions disappear also. Dr. Levy MS patients tend to have dozens of lesions, and many could be in the same pathway. So even if you remyelinate one, there could be one upstream or downstream of that lesion that's still impairing the function. In spinal cord injury, there is just one lesion, and they're trying to remyelinate just that one; you're correct about that. MSDF Are you familiar with the work by Basil Sharrack in England? There were about 10 patients, I think. They did myeloablative therapy and autologous bone marrow transplants, essentially as they called it, rebooting the immune system. That's obviously a stem cell therapy in a sense. Dr. Levy Absolutely, it is a stem cell therapy. The thought there is – exactly like you said – rebooting the immune system; taking out only the most immature stem cells that haven't been exposed to whatever the trigger of their disease was, taking those stem cells out and sparing them, holding them in the lab, then getting rid of the rest of the immune system in the patient's body and reintroducing those stem cells back; as you said, rebooting the immune system to see if we could return their immune system back to the pre-MS state and see if that has a better outcome. And, generally, those types of studies where we're really ablating the immune system have tended to have good outcomes; some patients are able to come off of therapy for years, but ultimately the disease comes back. And it could be years; it could be five, even up to ten years. And so we really have to understand why that is. If there's another environmental exposure or if there is just something really genetically encoded into the immune cells. MSDF Or, for example, if there's an EBV etiology, the Epstein-Barr virus is still there probably Dr. Levy That's right, so EBV may be that environmental trigger. MSDF One thing I don't understand about that is they reported, I think, in Science Translational Medicine, that people who had pretty significant disability – you know, using a wheelchair – could then walk again. It seems rebooting the immune system should not do anything to reverse or restore neural function. Dr. Levy That would be my expectation, too. So in any study where we're looking at effects on the immune system, I wouldn't expect the nervous system to have such a dramatic recovery either. That was a surprise. MSDF What else is there to say about stem cell therapy's messages to physicians who are asked about it, messages to patients who are interested in it at this point? Dr. Levy At this point, I would say that the verdict is still out, that the studies need to be completed, and that there are a lot of companies out there offering "stem cell therapies" to patients with MS, who are just looking for anything to improve their function. And that can be dangerous, because we don't really understand this science works, and there have been some bad outcomes reported in the literature from patients who are seeking this type of care from clinics offering "stem cell therapies." And I would just caution patients and caution doctors to wait until these studies are done and we have a better sense of how they work. MSDF There seems to be a lot of fly-by-night operations on the internet and overseas, and things like that, but even with legitimate trials I would guess there could be bad outcomes. What sorts of dangers are there in stem cell therapy? Dr. Levy There are two. One is that the stem cells will develop into tumors, because these stem cells are now able to proliferate, that's one of their features. So a concern is that they're going to proliferate uncontrollably into a tumor. And the second concern is that you're reintroducing a foreign cell – in some of the trials they're foreign cells – and that might trigger a relapse. So if you inject it directly into the spinal cord, could you then cause another inflammatory event in the spinal cord targeting those stem cells? So those are the two major concerns. MSDF Is there anything important to add, or that we've missed? Dr. Levy No, I would say that pretty much covers it. MSDF Well, thank you. [transition music] Thank you for listening to Episode 55 of Multiple Sclerosis Discovery. This Podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. MSDiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our president and CEO, and Hollie Schmidt is vice president of scientific operations. MSDiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to [email protected]. For Multiple Sclerosis Discovery, I'm Dan Keller. [outro music]