In Terry Mapes’ article “Searching for the Cause and Cure of MS” focused on the Tisch MS Research Center of New York and its annual free patient symposium. Several months later, the institution was granted what is very likely North America’s first FDA-approved stem-cell trial. It is considered a major advance in the research and treatment of MS.
MS is a chronic autoimmune disease of the central nervous system that affects approximately 2.5 million people around the world, including some 400,000 Americans. It impacts the human brain and spinal cord, and leads to myelin damage and neurodegeneration. As it is a relapsing or remitting disease with a wide spectrum of symptoms, it may take several years for a patient to get it properly diagnosed.
Brain World sat down with Dr. Violaine Harris, one of the study’s principal investigators, to learn more about the disease and the center’s progress in treating it. “Now that we got FDA approval, we can sort of talk about everything,” Harris says.
Brain World: What are the biggest challenges in MS research?
Violaine Harris: We don’t know what trigger initiates this cascade of autoimmunity; it seems to be a combination of genetics, environment, and chance. With genome-wide association studies — we can scan all of the genes in MS patients to find the ones most common in MS and then compare them to other people — we are looking for genetic underpinnings, which are probably related to how the immune system reacts to an environmental trigger. It could even be a virus. The Epstein-Barr virus, for instance, has been a candidate for a long time. While some 90 to 95 percent of adults have been exposed to it, 100 percent of MS patients are positive for it. This could suggest that you can’t get MS if you haven’t had Epstein-Barr, but it alone does not cause the disease. Other infectious pathogens have been investigated, but no strong evidence one way or another has been found.
The other major challenge of MS is to understand and hopefully target disease progression. MS starts out as an inflammatory disease. You can treat patients with steroids, and they’ll feel much better. But most of the therapies that we have are targeting the immune system. Over time, they stop working, and the patients steadily progress. It’s these progressions that we don’t understand. We know there is a neurodegenerative component, but we don’t really understand the specifics of how it works or have any good animal models for it, so it’s hard to develop therapeutic targets. That’s what we’re focusing on.
BW: In the last few years, what advancements have been made in understanding MS?
VH: I think we are getting a better understanding of the immune response in MS; it’s the direct result of having a fairly good animal model for the relapsing/remitting stage of the disease. The studies that come out of the animal work really tell us a lot about the immune system, because we can pick them apart and then translate that into human studies and therapies.
As similar as the immune systems are between a human and a mouse, they are still very different. And sometimes when we find therapeutic targets in mice and translate them to humans, we get the opposite effect. We’ve also had many successes, and a lot of drugs came out of those translations, but they don’t always work the way you think they would. The other drawback to this animal model is that it doesn’t model the progressive aspect of the disease.
BW: What about using an animal biologically closer to a human being, like a primate?
VH: We have a few nonhuman primate models. They better mimic MS in terms of the immune response and more in terms of the neurodegenerative components, but those models are very costly and are somewhat difficult to do. Most labs, like our laboratory, wouldn’t have the funds or the capacity — in terms of the animal facilities — to do it. There are specialized labs for that.
As a center, we have to prioritize different research projects and, up until now, using a primate model hasn’t been necessary. Even for our clinical trial, the FDA did not require that we use a nonhuman primate model, but I suppose if we got to a point where we could only answer a certain question using that model, we probably would apply for funding and try to raise the money to do that experiment. It’s very complicated, so we would want to make sure it’s worth it and will lead to something that’s going to impact MS patients.
BW: Since stem cells are the focus of the trial and seem to be very controversial, how do you bypass that and get funded?
VH: It’s hard to say if it’s specific to stem cells or the funding situation in this country generally. It’s pretty dismal. I think stem cells have been controversial because of the previous administration and the whole issue of embryonic stem cells. More and more, the research is moving past that and becoming less controversial. The stem cells that we are using are adult [bone marrow] stem cells. They are taken from the patient and are administered to that same person.
BW: From a scientific perspective, would embryonic stem cells be better?
VH: I’m pretty sure — yes. As I mentioned earlier, there’s neurodegeneration in MS. You have loss of myelin, so the neurons die, which means the cells that make the myelin — called oligodendrocytes — also die. The goal of stem cell research is to introduce cells that could actually replace the damaged ones. Embryonic stem cells, we know, are plastic enough to potentially replace both the neurons and oligodendrocytes. Bone-marrow stem cells can’t do that. From the animal models and other research that we’ve done, it doesn’t look like they are capable of going from a bone-marrow cell into a neuron.
They do a number of other things. Upon transplantation into the central nervous system, bone-marrow stem cells can actually migrate to areas where they are needed. They respond to a lot of the danger signals put out by damaged tissue in a similar way to how immune cells would respond to the same distress call. These cells use a lot of the same mechanisms to respond and migrate to areas of injury. The other thing that they do is they make a lot of proteins. They are growth factors and can basically initiate the body’s own mechanisms of repair.
BW: This sounds a lot like what the immune system should be doing.
VH: True. The immune system does promote repair. Although in a situation like MS, it’s an autoimmune response, and it’s chronic; it’s doing more damage than good over time. It’s very specific since there’s no autoimmune response outside of the nervous system.
BW: You and your team have been trying to identify the molecules involved in MSC-NP-mediated repair; can you tell us what that means in simpler terms?
VH: Right, so that goes back to when we were talking about how the cells migrate and then make proteins that they release into the area with damaged tissue. If we can understand which molecules are mediating this process of repair, then we can optimize the treatment. If we optimize the molecules, we might potentially not even need the stem cells. That’s one option.
This article was originally published in the Spring 2014 issue of Brain World Magazine.
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