Implications of Stem Cells in Multiple Sclerosis Research and Treatment

Podcast Transcript

Alex Rae-Grant, MD:  Neuro Pathways, a Cleveland Clinic podcast for medical professionals exploring the latest research discoveries and clinical advances in the fields of neurology, psychiatry, neurosurgery, and neuro rehab.

Stem cells can be recruited to repair damaged nervous tissue, offering an exciting potential avenue of therapy for patients with progressive forms of MS, as well as other conditions in which neural injury has occurred. In today's episode of Neuro Pathways, we'll be talking about the implications of using stem cells in multiple sclerosis research and treatment. I'm your host, Alex Rae-Grant, neurologist in Cleveland Clinic's Neurological Institute.

In an effort to explore the latest advances in neurological practice, I'm very pleased to have Dr. Jeff Cohen join us for today's conversation. Dr. Cohen is the director of the Experimental Therapeutics Program in Cleveland Clinic's Mellen Center for Multiple Sclerosis Treatment and Research. He's also professor of neurology in Cleveland Clinic's Lerner College of Medicine. Jeff, welcome to Neuro Pathways.

Jeffrey Cohen, MD:  Well, thank you for inviting me, Alex.

Alex Rae-Grant, MD:  You and I have known each other for a while. Before we get started, why don't you just tell our listeners a bit more about you? Where are you from? Where did you train? When did you begin your career at Cleveland Clinic?

Jeffrey Cohen, MD:  Well, originally I was born in North Carolina. My father was an academic psychiatrist, and he was at Duke University at the time. We then moved around several times as his career progressed. I went to medical school at University of Chicago, and then spent 14 years at the University of Pennsylvania. I came to the Cleveland Clinic in 1994.

Alex Rae-Grant, MD:  So you've been with us a few years? Anyway, today we're talking about a specific topic, the implication of stem cell use in multiple sclerosis research and treatment. You're a lead investigator in this area. Can you bring our listeners up to speed on the current state of MS treatment, and the perceived unmet need that providers and patients are facing?

Jeffrey Cohen, MD:  Well, we currently have more than a dozen approved disease-modifying therapies for multiple sclerosis. They represent a major advance in our ability to treat MS. However, there are still some unmet needs. One is that there are some patients for whom the available medicines do not achieve sufficient disease control, so there is a need for additional therapies for those patients. More importantly, none of our currently available therapies is very effective in progressive MS. Particularly, none of them restores tissue damage that's already occurred. So both of those unmet needs are areas were cell-based therapies, stem cell therapies, have been considered.

Alex Rae-Grant, MD:  I know that stem cells are a hot-button item in the public. We get a lot of questions about stem cells. Can you talk a little more about the state of stem cell investigation, specific to MS care, and get into a bit more detail about it?

Jeffrey Cohen, MD:  Sure, so I'm frequently asked by patients whether stem cell therapy would be appropriate for them. One of the things that becomes clear to me is that most people don't have a very good appreciation for the fact that there are many kinds of stem cells. One has to distinguish specifically which one is talking about. Stem cells are naturally occurring cells whose job it is to proliferate, create a supply of stem cells, and then also to develop, to differentiate into the various tissues of the body. We now know that there are stem cells in all the adult tissues whose job it is to repair damage that occurs to those tissues.

In MS specifically, we've thought about using stem cells to accomplish two things. One is to rescue a patient after a very potent, immunoablative chemotherapy, where in that situation the chemotherapy is the treatment for MS. It's a very potent anti-inflammatory treatment. Then the stem cell transplant, the hematopoietic stem cell transplant, is intended to lessen the adverse effects of the chemotherapy. That's one approach that's been considered in multiple sclerosis.

The other approach is to use stem cells or medications that work through stem cells to augment the normally occurring repair that we know occurs in MS but frequently is inadequate to keep up with the ongoing damage.

Alex Rae-Grant, MD:  I know you've done some preliminary work and continuing work in mesenchymal stem cells. Do you want to talk a little bit more about that particular kind of stem cell?

Jeffrey Cohen, MD:  Sure, so I think it's important for the listeners to be familiar with the mesenchymal stem cells because that is the therapy that many of the free-standing, commercial stem cell clinics are offering. Mesenchymal stem cells are cells that normally are found in most tissues in a perivascular location. Their role is to modulate ongoing inflammation in tissues and to promote repair once damage has occurred.

Mesenchymal stem cell transplantation has been tried in a number of disorders. Most of the experience is in inflammatory bowel disease, ischemic heart disease. It's also been tested in a number of neurologic conditions including multiple sclerosis. In that situation, there have been now quite a few small pilot studies, all of which have shown good safety. Most of shown some indication of benefit, but the benefit's been modest.

One of the things that we've learned is that there are a great many practical uncertainties. What dose of stem cells we should use? By what route they should be administered? How best to grow them in culture, so that they're effective? Whether they can be frozen? All of those things are very important, unanswered questions. That's why I caution my patients that it's somewhat premature to pursue mesenchymal stem cell transplantation outside of a clinical trial. There are some recent studies that suggest that growing the cells in a particular way, to augment their ability to promote repair, and also administering multiple doses via a spinal tap may be the most effective approach.

Alex Rae-Grant, MD:  It sounds like there is still quite a bit of research work to develop the foundation for stem cell use in MS.

Jeffrey Cohen, MD:  Precisely. There's a great deal of interest, but there's still many unanswered questions.

Alex Rae-Grant, MD:  Where do you think the next set of steps would be in terms of stem cell research both at the clinic and elsewhere? What sort of building blocks need to occur before we're kind of there?

Jeffrey Cohen, MD:  Well, I think in the case of mesenchymal stem cells, there are some ongoing studies that will build on the previous studies, and I think show more clear-cut benefit. Those studies are currently underway.

Jeffrey Cohen, MD:  A second approach that I think looks very promising is to use medications and small molecules that work via the intrinsic stem cells rather than administering the stem cells themselves. The advantages are that those molecules can be manipulated and developed, so that they penetrate the central nervous system, stimulate the stem cells that are already there but present many fewer technical challenges.

The third area that I think listeners are going to see a great deal of work in is in hematopoietic stem cell transplantation. There have been quite a few studies that showed that hematopoietic stem call transplantation is a very potent, a very efficacious treatment for multiple sclerosis and other autoimmune diseases. That the benefit is long lasting and may persist for five, 10 years without any additional therapy.

However, there are a number of uncertainties. One is that hematopoietic stem cell transplant still is a rather aggressive therapy with a great many potential adverse effects. Luckily, those mostly occur at the time of the transplant, so the risk then lessens over time. It's also a rather expensive therapy. Again, all the cost is up front, so it actually becomes cost effective compared to disease-modifying therapies after two to three years.

The final issue is that, although there have been a great many studies of hematopoietic stem cell transplant, all of them had some shortcomings. Either they were K-series or uncontrolled small phase II studies. Or in the case of the two randomized trials that have been performed, the comparator arm was not ideal. It was either mitoxantrone, which is drug we don't use anymore to treat MS, or was disease-modifying therapies that we would not consider our most potent options.

The current state of hematopoietic stem cell transplant is that it's probably an appropriate option, as a last resort for a patient who has very active lapsing MS, that's not responded to available therapies. But for me, that's not really the most interesting question. The most interesting question is whether hematopoietic stem cell transplant might be an option for a patient in whom one is considering one of our potent monoclonal antibody therapies. That question is going to be addressed in five, ongoing, randomized controlled trials. One of which we'll be participating in at the Cleveland Clinic.

Alex Rae-Grant, MD:  Jeff, getting down to nuts and bolts, how would you advise your colleagues, who have a patient in front of them asking for stem cells, some place down the road? I mean, how would you advise them to answer that question?

Jeffrey Cohen, MD:  Well, that actually is a very common question. I'm, in fact, asked that almost on a daily basis, "What about stem cell therapy for me?" What I tell patients is that although there's a great deal of interest and a great deal of activity in developing stem cell therapies, currently no stem cell-based therapy is appropriate as a standard treatment for multiple sclerosis.

Alex Rae-Grant, MD:  Maybe in the next five years we'll have a better sense of that particular approach to MS treatment?

Jeffrey Cohen, MD:  I think so.

Alex Rae-Grant, MD:  Well, Jeff, you've been a leader in research in MS for the last many years. Any sort of overarching changes that have occurred over this time? It's been pretty remarkable.

Jeffrey Cohen, MD:  Well, I don't want to date myself.

Alex Rae-Grant, MD:  Go ahead.

Jeffrey Cohen, MD:  When I first got into the field, there were no available disease-modifying therapies. Now, we have more than 15 options. That's been a major improvement in our ability to treat relapsing multiple sclerosis. The big unmet needs now are to treat progressive MS and to restore damage. I think we're starting to get a handle on how to do that. I think the next few years will show us how to do that in a better way.

Alex Rae-Grant, MD:  Well, Jeff, it's been a very interesting, exciting time in MS research and treatment. I think we all look forward to seeing how the research that you and others are doing evolves. Thank you for your time in discussing this research effort.

Jeffrey Cohen, MD:  Thanks for talking with me.

Alex Rae-Grant, MD:  This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodast or subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you get your podcasts. Don't forget you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's consultqd.clevelandclinic.org/neuro or follow us on Twitter, @CleClinicMD, all one word. That's @C-L-E-Clinic M-D on Twitter. Thank you for listening. Please join us again soon.