Eva L. Feldman, M.D., Ph.D., F.A.A.N., F.A.N.A
Wednesday, November 5, 2014
Listen to Episode 8:
Seth: Hello and welcome to episode 8 of ALS Crowd Radio. I’m your host, Seth Christensen, here as always with my co-host, Amy Christensen.
We are thrilled today to have as our guest, Dr. Eva Feldman, of the University of Michigan. Amy?
Amy: Dr. Feldman received her MD and PhD from the University of Michigan and completed a neurology residency at the Johns Hopkins Hospital and returned to University of Michigan for a Neuromuscular fellowship.
In addition to her clinical practice and position as the Russell N. DeJong Professor of Neurology at the UM Medical School, Dr. Feldman is Director of the A. Alfred Taubman Medical Research Institute, and is the Director of Research for the University of Michigan ALS clinic. She runs her own 30-scientist laboratory, the Program for Neurology Research & Discovery, and is the Principal Investigator of the first-ever FDA-approved human clinical trial of an intraspinal stem cell implantation therapy for ALS.
Dr. Feldman has published more than 300 original peer-reviewed articles, 60 book chapters and three books and is the Principal Investigator on five major NIH grants. She is the Past President of the Peripheral Nerve Society and serves as President of the American Neurological Association from 2011 to 2013. She has been listed in The Best Doctors in America for the last 15 years.
Seth: Dr. Feldman, are you with us?
Dr. Feldman: Oh, yes. I’m definitely with you. Thank you so much for having me today.
Seth: Well, it is our honor and thank you for making time. I believe we already have a record number of callers on the line so that is a good sign for today’s discussion.
As our topic, we have chosen ALS stem cell research but thought we would open with a broader question. We have known about ALS for quite some time, are we learning new things about ALS today?
Dr. Feldman: Oh, we certainly are, Seth. Every day we are learning something new about ALS. In fact, in the last three to five years, I think the new data, the new research and the new clinical findings that are coming out probably surpass what we have learned in the previous 20 years. So now we understand new genetic causes of ALS and that’s given us new clues on why everyone who has ALS may get it, so the sporadic cases of ALS.
We are learning new imaging tools, we’re discovering new reasons that there may be environmental and occupational exposures to ALS and then new therapeutics. So the field is rapidly changing and in my 25 years as an ALS clinician-scientist — so it’s a long time — I have not seen such progress like the progress I’ve seen in the last three to five years. It’s really remarkable.
Seth: We have heard that sentiment echoed among your peers and are thrilled to hear it as an ALS patient community.
Now your particular focus on research is very broad and deep in a number of areas. Do you consider yourself a specialist in a particular area of ALS research?
Dr. Feldman: Well, I’m interested in three broad areas of ALS research. One area that I’ve been interested in for a very long time is if there’s an occupational or an environmental exposure that may predispose someone to developing ALS.
So we currently have a grant from the Center for Disease Control where we’re doing a very detailed study asking those very questions of our ALS patients and in parallel, measuring levels of like pesticides and different environmental exposures in their blood and their hair. And coming up with what I am certain will be new insights into answering that question. So that’s one area.
The second area I’ve been very interested in is developing new ways of imaging the brain and the spinal cord to better diagnose individuals very early in the course of ALS. Frequently it takes a long time, at least a year — the average is a year — to make the diagnosis. And if we could have a way to image the brain and the spinal cord with our new techniques, we can make the diagnosis sooner. And why do I want to make a diagnosis sooner? Well, that’s my third area of interest. I’m very interested in therapeutics, particularly cellular therapeutics or stem cells and I’m very interested in the potential beneficial role of stem cell therapy in ALS. And I have evidence, both based on my clinical studies in patients as well as my preclinical studies in animal models of ALS, that the earlier we can perform stem cell transplantation, the more likely it is to have the benefit for ALS patients.
So those are my three broad areas of interest.
Seth: Excellent! I know we could dedicate our show to each of those areas at least but for today, we’d like to focus in on your stem cell experience and ask why stem cells? What is the promise of this area of research?
Dr. Feldman: I will tell you a story, Seth. I turned to the idea of stem cells approximately seven years ago when I had spent almost ten years in a clinical trial that failed in ALS — a clinical trial with a drug known as myotrophin or IGF-1. And I had spent almost a decade doing the preclinical work and then working on developing the clinical trial and doing a series of clinical trials.
And I felt that that experience led me to believe that it’s going to be difficult for just one drug to be beneficial solely in ALS so we needed something, a combination of drugs, or what about stem cells. Because stem cells, in a way, are really quite remarkable in that they can go into an environment and in the case of ALS, the stem cells can enter the — I’ll call it — ALS environment, whether it’s in the brain or the spinal cord. They can secrete growth factors which are very good for disease tissue and makes it healthier. They can form synaptic contents, they can actually even produce neurotransmitters, they can become nerve cells, they can become supporting cells. So the promise of stem cells or my interest in stem cells began when I had the kind of realization that it’s never going to be just one drug that’s going to really truly provide long-term benefit in ALS. But we need to go away from the single drug idea to what I’ll call a cellular therapy and that’s where stem cells come in because they have so many beneficial aspects to them.
Seth: How long has the ALS research community been really interested in the stem cell research?
Dr. Feldman: I think for the last decade there’s been interest. For the last five years, there’s been a great deal of interest. We entered our first patient in our FDA phase I approved stem cell trial in January of 2010. We’ve now completed both a phase I and a phase II trial. There are now other very good individual ALS clinics and groups of ALS clinics that plan to do similar stem cell trials but maybe using different types of stem cells.
So the idea that stem cell therapy could potentially be both safe and beneficial in ALS has taken traction and so there are several other new proposed trials besides our own. So I’m very excited about that and look forward to not only now doing the next phase of our trial but also hearing and understanding new and different ALS stem cell trials that are coming on board.
Seth: Wonderful. Could we talk for a moment about your, now famous, Neuralstem trial? Could you outline that experience for those of us who are new to stem cell research?
Dr. Feldman: Of course. So the Neuralstem trial has now been completed in both what we’ll call a phase I trial and a phase II — those are the designations by the FDA. So a phase I FDA trial is completed for safety and it’s really safety alone which, really, not looking at efficacy but looking at if the procedure is safe. And in that particular trial, we entered 15 patients for a total of 18 surgeries. So three patients got double transplants and we were able to safely show that we can inject stem cells directly into the spine of ALS patients, in the lower spine called the lumbar spine area as well as the upper spine known as the cervical area. And in that trial, we injected up to 1.5 million stem cells and we continued to follow those individuals over time who remain active in the trial. So that is the phase I.
So the phase II trial then is designed to continue to look at safety but in this case, we also wanted to increase the dose of stem cells as well as do more stem cell injections into the cord. And I’m pleased to report in that trial which we completed July of this year. We again entered 15 patients and did 18 surgeries. Previously as I told you in the phase I trial, the most stem cells that one patient received was 1.5 million. In this phase II trial, we got up to 16 million stem cells, given 8 million stem cells in the low back, and 8 million stem cells in the upper back or the upper part of the cervical cord, the spinal cord. These patients are now being followed, again, safety. We have shown this procedure is safe in both phase I and phase II.
And now on phase II, we also begin to look at what we call exploratory clinical efficacy, kind of medical lingo for “Is there a signal, a therapeutic signal? Do we see a difference in the patients who’ve received 8 to 16 million stem cells in the course of their disease?” So now we’ve just completed this trial and we don’t have, we’ve not looked at the data yet. We will not look at the data until six months after the last patient was entered but that’s going to be very exciting information for us to have at the end of the phase II trial and has helped guiding us as we plan the next phase of the trial which we call phase II B.
Phase III, when we complete the phase III trial, that’s the definitive trial, and that will say whether or not this therapy can go out of the research arena into the more general clinical therapeutic arena where it could be available for all patients.
Seth: Thank you for that explanation. So it’s six months until we look at the data, what would be the ideal timing be for phase II B or a phase III?
Dr. Feldman: Well, I’d like to say six months from now if possible.
So the ideal timing will be we will need to carefully look at those data and we are hopeful to have an application in place in the winter-early spring of 2015 with the goal of beginning recruitment as soon as we can. Again — Seth, you need to hear this — we feel the same, I feel the same sense of urgency that you feel. Everyone who works with me does. Everyone who has spent their life trying to understand ALS and develop therapeutics feels and embraces the sense of urgency as the ALS community does, because we’re all part of the same community, the sooner the better but we need to look at the phase II results before we can put that next application in.
Seth: Excellent! Let’s keep the pedal to the metal on this.
Dr. Feldman: We definitely will.
Seth: You mentioned a moment ago other trials that are using different types of stem cells. We had Dr. Jeffrey Rothstein on a few weeks ago to talk about IPS cells.
Dr. Feldman: Wonderful.
Seth: Can you speak about the type of cells we used for the phase I and II Neuralstem trial?
Dr. Feldman: Yes. So interesting because the name of the biotech company who has generously supplied the cells and has funded a great deal of this trial is Neuralstem and these are actually neural stem cells. So these are stem cells that have the fate to become some type of nerve cell in the body when they’re transplanted. And what we find, Seth, is when we place these stem cells in the spinal cord of an ALS preclinical model, these stem cells, about half of them become nerve cells and the other half become supporting cells of the nerve cells.
And what’s also kind of a segue just to explain a little bit more about why these cells are likely so therapeutically potent is, again, in the ALS spinal cord, the large nerve cells are undergoing a death and the surrounding cells look very inflamed and angry so I call it kind of a bad neighborhood, the neighborhood looks like in disarray. And you put the stem cells in and the stem cells form again these contacts on the sick nerve cells and begin to nurse them back to health and also all the inflammation around the sick nerve cells go away, the stem cells kind of clean up the inflammation also.
So these neural stem cells become nerve cells and also these glial cells and they have very, very strong therapeutic potential in the spinal cord.
Seth: Now we hear a lot socially about embryonic versus other derived stem cells. Could you explain the difference between the promise of different cell lines?
Dr. Feldman: I’ll be happy to.
So first, I think it’s important to understand what embryonic stem cells, how they are created, because I believe there’s some misconception there. So in Invitro fertilization clinics, a man donates sperm, a woman donates egg; in a small petri dish the two are put together and embryos are formed. Many of those embryos are taken for transplantation into the woman to, of course, have children. Some are frozen but most are discarded, literally put down a disposal. And so those embryos that would otherwise be discarded can be donated.
So those donated embryos are then placed in a petri dish and on day 5, a small part of the donated embryo known as the inner cell mass is then taken and put in another petri dish and that’s the beginning of what’s known as an embryonic stem cell. And those cells have the ability to become any cell in the body. They’re called totipotent, meaning they can become any cell in the body. So that’s an embryonic stem cell.
Early on, Seth, in our work, in the preclinical and the animal models of ALS, we looked at embryonic stem cells as the source of therapy but come any cell in the body, when we put them in the spinal cord, many of them became nerve cells and glial cells but they also could become other types of cells that we didn’t want. So for our purposes, these cells were not good for therapies.
As I mentioned, in the dish you can grow the embryo to a later stage and or you can receive donated fetal tissue. And then tissue that’s been donated, you can take the small piece, for example an area that was going to become the spinal cord or the brain from a two- or three-week donation and those can become stem cells, those are called progenitor cells or, in this case, neural stem cells. Or you could take some that would definitely become a muscle cell, et cetera. So that’s another type of stem cell, a progenitor cell.
Another type, of course, are adult stem cells and the use of adult stem cells are mesenchymal stem cells which are from the bone marrow of patients. It’s currently being done and there’s a clinical trial about that, I’m happy to tell you about that, that that’s ongoing for ALS.
And then the fourth type that’s commonly discussed are these IPS cells and I know that Dr. Rothstein just talked about those. And that’s when you take a small, either your own blood cell or a small skin cell, and you turn that into an embryonic-type stem cell.
Seth: I’m sure we’re just scratching the surface here, thank you for that.
So to clarify the Neuralstem trial, were they progenitor cell trial?
Dr. Feldman: Yes, it is. It was and will continue to be. And this is a progenitor cell line, this is a stem cell line that was developed over ten years ago and has been thoroughly studied which is very good for us and is also made in what we call GMP grade, good manufacturing practice grade, which the FDA insists on before you can use it in a clinical trial.
So we chose this to work with Neuralstem because we saw these cells have been the type of cells that would be particularly therapeutically beneficial in ALS. And were ready to go too, I should throw in, and were ready to be used.
Seth: Excellent, excellent. We will pause for a second to have Amy invite listeners.
Amy: Hi, callers! Please call in to 516-590-0362. And to indicate that you have a question for Dr. Feldman, please push the number 1 and we’ll know you’re ready for the questions at the end of the show.
Seth: Thank you, Amy.
Now, Dr. Feldman, we have this exciting trial going on. What other trials are you involved with currently?
Dr. Feldman: You mean my own or the other ALS trials that we’re doing or do you want me to talk about the other stem cell trials that other individuals are doing, Seth? What do you think people would rather hear about? Maybe the other stem cell trials?
Seth: Perhaps that would be the best use of our focus area.
Dr. Feldman: Yes, I think so, because the other trials that I would discuss would be unique to our clinic while the stem cell trial, our own stem cell trial that I just discussed, the next phase will be more broadly available to everyone in the United States which I think is very exciting.
And there are three other trials, one that’s ongoing and two that are in the active planning stages that should begin shortly. The one trial that’s ongoing is a trial that’s been done by the University of Massachusetts. I also believe it’s Massachusetts General Hospital and Mayo Clinic and that’s the mesenchymal stem cell trial where a patient will come in, a bone marrow biopsy will be done. The mesenchymal stem cells, so the bone marrow stem cells are taken from their own bone marrow and then they are processed and they are injected back into the patient’s spinal fluid. It’s the fluid that surrounds the spinal cord and the brain. And so that is an active ongoing protocol currently. It’s a different type of approach that we are using in our Neuralstem trial, of course, but I think it’s an exciting new venue.
Two other trials that are proposed and I think will begin shortly. One is being done at Cedars-Sinai in Los Angeles by Drs. Clive Svendsen and Robert Baloh. This particular trial is similar to the trial that we have done with Neuralstem in that in this trial, they’re going to inject stem cells into the low back, the lumbar part of the spinal cord. But these stem cells, they’re not neural progenitors like the stem cells that I discussed with you. These are progenitors for the supporting cells of the nervous system known as astrocytes, so it’s a different type of stem cell. And another exciting part of these stem cells is that they produce a lot of one particular growth factor known as GDNF which is very neuroprotective to the spinal cord. So that stem cell trial, I believe, is going to start in the near future.
A third trial is actually being done at Johns Hopkins and maybe Dr. Rothstein mentioned it with Dr. Nick Maragakis and he too is doing a different type of stem cell and I believe that his approach is going to be similar to the approach that we both have used and Dr. Svendsen andBaloh are using in terms of directly injecting stem cells into the spinal cord.
So we go from no stem cell trials in 2009 and we fast forward five years and we now have one active trial doing intraspinal injections, our trial; the mesenchymal trial, doing the injections around the spinal fluid; and then two new proposed trials. So the field’s moving very quickly.
Seth: We love to hear that. I believe the mesenchymal trial is commonly known as the BrainStorm trial?
Dr. Feldman: Yes, it’s commonly known as the BrainStorm trial. I just wasn’t sure since I didn’t have BrainStorm’s permission to mention their name if I could but you did, Seth, so good.
Seth: Yeah. I hope they’re not too upset with me. And I am not aware of the other two common names but we can —
Dr. Feldman: This trial at Cedars-Sinai with Dr. Svendsen and Baloh, those cells were developed by Dr. Svendsen himself and that trial was being funded by you know how California makes a very large investment in stem cell work, and so it’s actually being funded by the State of California which I think is very exciting and very transformative. So that’s actually being funded by the State of California.
And then in a similar vein, the trial being done at Hopkins, I guess that trial I believe is being funded by a company known as StemCells, Inc. I believe that’s correct. We may need to fact-check that.
Seth: Okay. Excellent. Thank you for that high level of review. I know we have a record number of callers and I would like to get to those questions. I know you were very gracious and interested in answering questions.
We will go to our first caller. Caller ending in 0200, you’re on the air with Dr. Feldman. Please go ahead.
Dr. Feldman: Hi!
Caller: Hi! I guess my biggest question is for those that have ALS and are interested in participating in trials, how do they become involved in them?
Dr. Feldman: So multiple different ways. For those patients who have ALS, they are likely being seen in an ALS Association-certified center or an MDA-certified center, and those certified centers, the centers themselves have a list of all the available trials. And for specifically about the stem cell trial that I’m telling you about the next phase, as I mentioned, we’re going to make that trial available nationally. Previously you have to be geographically located close to one of the three centers that were actually doing the surgeries, that’s now going to be more open.
And information on that trial will be available on the ALS Association website, clinicaltrials.gov is another good source and also, in our particular case, the Neuralstem website. But if you go to the ALS Association website, the MDA website, clinicaltrials.gov, that lists almost all the trials. Then your own physician will also of course be able to be helpful in the ALS or MDA clinic.
Caller: Thank you very much.
Dr. Feldman: Oh, you’re welcome.
Seth: All right. Thank you, Caller 1. We’ll keep going down the list and as a reminder, if you have a question for Dr. Feldman, please hit the number 1 and we will enter you in the queue.
Our next caller ending in 8760, you are on the air.
Caller: Hi, Seth, this is Allison. We met in Florida, hello. And hi, Amy, if you can hear me too.
And Dr. Feldman, I want to first thank you for dedicating your career to finding a treatment for ALS. My husband was diagnosed last year and he’s just 41 years old and so of course we are very dedicated in wanting to find a treatment for the disease. I know that you’re specifically talking about stem cells but I was really interested in one of the first things you talked about, about your clinical interest including the environmental and occupational factor that may be contributing to ALS. And I was wondering if there is anything that you have seen in the research that you have done or preliminary data that’s been collected.
Dr. Feldman: Right, that’s a wonderful question. Yes, we just published a paper. It’s a very preliminary paper, so I’m glad we’re both using the word preliminary, showing that pesticides particularly organophosphates, individuals who have had that exposure have a greater likelihood of developing ALS.
And so that’s like the first tick in the occupational environmental exposure box that we have fairly confirmed evidence on. And that’s only the beginning. We also have preliminary evidence on what are called flame retardants. So exposure to both organophosphates pesticides and flame retardants and individuals who had exposure to those two compounds or substances, their likelihood of developing ALS was up to two-to three-folds higher.
So this is preliminary, this brings up though a great point. Have you heard about the National ALS Registry?
Dr. Feldman: Yes. So that is a fabulous thing that our government is doing. So that is a registry of all living ALS patients. And when you go to register, there’s about a one-and-a-half hours’ worth of forms to fill out or questionnaires and they’re surveys about occupation, surveys about your exposure, surveys about where you live in terms of is that meaningful if you live near a lake, near a toxic dump, et cetera.
So I encourage everyone to enter the National Registry because those data, along with I think our own study, are going to help answer these important questions.
Caller: Thank you so much.
Dr. Feldman: Oh, thank you for calling.
Seth: Thank you, Allison.
We will continue down our list. Caller 3 ending in 0899, you are on the line with Dr. Feldman.
Caller: Oh, hi! Thank you. Dr. Feldman, thanks for your work. It’s wonderful.
Dr. Feldman: Thank you for the comment.
Caller: I just wanted to know about the qualifications for an ALS patient to participate in a stem cell trial.
Dr. Feldman: Certainly, that’s a wonderful question. Thank you so much for asking.
We don’t specifically know yet because as I mentioned, we are in the next step of preparing the next application and we’ll of course again wait the phase II data for final preparation. But we anticipate, we would like to enter individuals earlier in the course of their disease so three years or less which brings me back to my very first point of the program, that’s why early diagnosis I think is so important, so three years or less. And we are interested in entering patients who have a forced vital capacity, a respiratory capacity of at least 60% and that’s something that patients are tested for in their clinic regularly. And we are interested in entering patients who do have good speaking and swallowing so they don’t have a great deal of trouble speaking and swallowing.
So those are going to be the entry criteria. I think the key one is less than three years of disease and then being able to have a forced vital capacity of 60%. I should tell you, again, we used to use to have to live in a certain place like Michigan or Georgia or Massachusetts in particular but that will no longer be a requisite at all.
Caller: I have one more follow up. In following some of what Seth and Amy are doing, looking at ALS Crowd, they’re looking at bringing in ways of collecting data and so I’m interested in your first point of that kind of early identification of the environmental factors and any thoughts on maybe how new ways of collecting data.
Dr. Feldman: Yeah. I think that’s just a great question.
I’ll go back to the National ALS Registry because they just published their very first paper on the National Registry. And that is going to be a way for us to collect big data on all currently living ALS patients and that is going to be extremely valuable and they’re going to make that data open to all interested individuals and academia so that we’ll all be able to access that data to better understand. Again, this in particular, environmental occupational exposures. But they also have a subset of individuals who are going to their homes and they’re actually drawing blood like we are doing, accessing hair, nails, and trying to understand in the home environment more the occupational exposure.
So now you couple that registry with what’s also being done by the National Institute on Aging as one example where they are trying to collect blood and do genome sequencing looking at all of your genes, that 16 billion reads as we call it, I mean, it’s a huge set. And they’ve done that now in over 5,000 patients and they are hopeful to triple that number. So if you combine the data of the genes with the data of the exposures and the Registry data, we might really begin to get new insights into ALS. So combining and looking at big data are very, very important.
And if I may add and then I’ll stop is I think organizations such as PatientsLikeMe can also be very pivotal in providing data for academia and for these big data sets.
Seth: Thank you, Caller, for your question.
Dr. Feldman, we could spend hours on any of these topics but I wonder, as we wrap up over the next few minutes, if there are any other projects that you are excited about and feel we should mention?
Dr. Feldman: Yeah. I’ll mention one last before we close for the afternoon. Before I do mention I want to thank you again for having me and tell you what really an honor it is to talk to you and to get to talk to other individuals from the ALS community as together as a team we try to better understand what causes ALS and come up with new therapies. So thank you, Seth and Amy, very much.
And so to end, I’ll tell you another project that I’m pretty excited about. And it definitely ties in with the environmental exposure project in that what we now know is that you and I are born with one set of genes, one set of DNA. But over time, what we do, what we’re exposed to changes that DNA and that field is known as epigenetics. And epigenetics is how our DNA changes over time due to what we’re exposed to as during our lifetime and those changes in the DNA actually then result in changes in what are known as RNA and protein that come from the DNA.
And so what we have seen is that in patients with ALS, there’s a clear what I’ll call epigenetic signature, a clear change in their DNA. And we believe again it’s due to environmental exposures but that is helping us try to understand how, for example exposures to pesticides and flame retardants, how that would cause a result in developing ALS so to understand what I’ll call the mechanism of the disease. So this field of epigenetics is an area that my laboratory is very invested in and we think will lead to new therapeutic targets in ALS.
So I can end with that, with my enthusiasm for cellular therapy, stem cells, but also then for this understanding of occupational exposures and this field of epigenetics.
Seth: Thank you for mentioning that project.
If we could ask one final question that we ask on all our shows is what is the greatest opportunity for our listeners to get involved?
Dr. Feldman: I believe the greatest opportunity is to get involved locally, so to get involved locally with either your ALS chapter, your ALSA chapter in particular or possibly your MDA chapter and or in your local ALS clinic and or any very local groups that are involved. Like here we have something called Ann Arbor Against ALS, A2A3 we call it, and it’s a local group that works with the ALS Association and the MDA.
And I think local involvement is very important. Why get locally involved? To raise awareness. This Ice Bucket Challenge has taken a disease that you and I know well but many people have never heard of and is now made nationally understood. So when you get locally involved, you increase awareness. You may or may not increase funding for the disorder but importantly you connect with other individuals who know and understand the disorder. So the more that we can increase awareness, I think, it’s extremely important. If everybody who listens to this program could, if they’re not part of the National ALS Registry, register and tell two or three other ALS pals to register, that could make a tremendous importance.
So local, local, local. I think to get involved locally with your organizations and what they are doing is by far the most important thing one can do. And I really do think together we can really come up with an understanding of this disease and I always say, “Wouldn’t it be great to have an ALS-free world?”
Seth: Indeed, indeed. And thank you for dedicating your career to our community. We deeply appreciate your dedication, creativity, and life focus and we applaud your efforts.
Dr. Feldman: Thank you so much. It is truly an honor, I have to tell you, and a pleasure to work with the ALS community. You are the reason I do what I do every day, Seth, so thank you so much for everything you do for the ALS community. And you too, Amy, thank you so much.
Dr. Feldman: Okay. Well, goodbye, everyone. Okay. Thank you again.
Seth: For our listeners, a full transcript of this episode will be available on ALS Crowd over the next couple of days. Thank you to Dr. Eva Feldman your time.
Bye for now.