Eva Feldman, MD, PHD — ALS and Stem Cell Therapy

Dr. Eva Feldman
Eva Feldman, MD and PhD, works closely with her research team to seek cures for some of the world’s most devastating diseases, including Alzheimer’s, diabetic neuropathy and amyotrophic lateral sclerosis (ALS), which is often called Lou Gehrig’s disease. The latter causes progressive weakness, muscle atrophy and respiratory difficulties.

As a neurology professor at the University of Michigan (U of M), Feldman helped pioneer the initial clinical trial of intraspinal stem cell transplantation in patients with ALS. In the first of a three-phase trial, 100,000 stem cells were transplanted into each patient via a spinal cord injection. And each patient received either 5 or 10 injections.

Although Phase I was to simply prove the procedure was safe, a subgroup of patients experienced signs that their ALS progression had been interrupted as a result of receiving stem cells. Given the promising results of Phase I, it seems there is exciting potential in harnessing stem cells to slow down or completely arrest the progression of ALS and other enigmatic diseases.

Recently, ABILITY’s Christoph J.B. and Chet Cooper spent an afternoon learning more about Feldman and her work.

Christoph J.B.: As I understand it, Phase I of this trial was the first of its kind in the world.

Dr. Eva Feldman: Right. With Phase I, we’ve shown the safety of the procedure, which was called a risk escalation trial. We transplanted patients in groups of three and each group had better neurologic function after the transplant than before it.

The first 12 operations were in the lower part of the spinal cord and the last six operations were in the upper part—the cervical cord. The idea behind injecting the cervical cord is to be able to preserve the large nerve cells that control breathing, as most patients with ALS eventually die from the inability to breathe.

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We’ve submitted Phase II of our trial to the Food and Drug Administration (FDA), in which patients will be given injections at both Emory University and the U of M. We hope to do two patients a month, one at each institution, for a total of 36 patients. [Editor’s Note: Not long after this interview, Phase II was approved by the FDA in a process where Feldman’s team submitted their plans, responded to FDA suggestions, resubmitted their plans a second time and responded to yet another set of suggestions.]

Chet Cooper: Can you talk more about how stem cells are transplanted? Are they injected with a needle, or is this an actual surgery?

Feldman: It’s definitely surgery: We expose the spinal cord, taking away the bone and peeling back the cord’s other coverings. Then we take this very thin needle and put it into the spinal cord to inject the stem cells.

Cooper: This isn’t what you’d call “minimally-invasive” surgery.

Feldman: The spinal cord blood vessels that we have to bypass are different in everybody. If we went in there and hit a blood vessel rather than going directly into the spinal cord, we would produce what’s known as a hematoma and then you’d get a lot of blood. So unfortunately we can’t do a minimally invasive procedure with this type of surgery. Now, I will tell you that we’re working with our bioengineers here to address this, because we would prefer to do a less invasive procedure. Currently we are at the development stage.

J.B.: How far off is Phase II?

Feldman: If all goes well, we should be operating by the summertime.

J.B.: Oh, that’s great.

Feldman: Yes, we submitted a protocol to the FDA that they’d never seen before, so it’s been challenging for them and with that challenge comes the opportunity to set new standards for cellular therapeutics.

J.B.: In 2008, Proposition 2 passed in Michigan, which approved the acquisition of embryonic stem cells. I know you played an active role in getting that legislation passed. How did Proposition 2 change the game?

Feldman: Michigan was one of a handful of states where it was still illegal to create embryonic stem cell lines—even though it was federally legal. When we could not get it past the legislature, we sought to get it in on the ballot. Al Taubman, for whom the A. Alfred Taubman Medical Research Institute at U of M is named—and which I run—personally invested over $6 million to get the issue on the ballot. He helped spread the word that instead of destroying the embryos that are created in in-vitro fertilization clinics, we wanted to give parents the option of donating those embryos for the creation of new stem cell lines.

J.B.: Can U of M researchers create their own stem cell lines now?

Feldman: We can now create our own stem cell lines by using private donor money only. It is against the law in the United States to use National Institutes of Health grants to create new lines, but you can use these grants to study the lines after they are created. At the U of M, we have the Consortium for Stem Cell Therapy, where we create new human stem cell lines and we’re particularly interested in creating what are known as disease-specific lines. In an in-vitro fertilization clinic, the woman donates an egg, the man donates sperm and embryos are created. A single cell can be taken from the embryo and undergo genetic analysis to test for over 130 inherited diseases. Those embryos that do not have inherited disease get implanted into the woman. Those embryos that do carry the genetic defect are used to create new embryonic stem cell lines, only of course, if the parents fully consent. The Consortium has created disease specific stem cell lines for Huntington’s disease, Charcot-Marie-Tooth disease and muscular dystrophy, to name a few.

J.B.: Is your team the only one in the world doing the ALS treatment procedure that you’re implementing in Phase II?

Feldman: No, a group of researchers in Italy who observed our surgery at Emory have begun a trial. They’re looking at a different stem cell line, but using the same surgical device that we developed to stabilize the spine and administer the cells. A team in Mexico wants to do essentially the same trial that we’re doing and has the backing of the Mexican government. These are two places that I think are going to be fairly well regulated in terms of quality.

The Miami Project to Cure Paralysis plans to use our methods in a spinal cord injury trial as well, and just got FDA approval to start Phase I. I was down there for a couple of days and it was very exciting. And last but not least is a group led by Clive Svendsen at Cedars-Sinai in Los Angeles, which is taking our same approach but using a different stem cell line in ALS patients. So there are three ALS trials and one spinal cord injury trial.

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J.B.: Let’s talk about the work you did at the University of California San Diego (UCSD). A UCSD scientist worked with rats, giving them ALS-type symptoms and then arrested those symptoms. You helped pioneer this study, correct?

Feldman: We did. A man named Dr. Martin Marsala at UCSD was looking at spinal cord transplantation for spinal cord injury and when I began to work with him, I said, “We need to look at spinal cord transplantation for Lou Gehrig’s disease or ALS.” So we began to collaborate using the techniques he had developed for spinal cord injury in animal models of ALS. I brought on board a neurosurgeon, Dr. Nicholas Boulis, who had been my fellow for three years here at the U of M and the team grew.

Given the political climate at that time, it was best to do the trial at Emory instead of at U of M; also Dr. Boulis is at Emory and it was hard for him to commute to Michigan. Though we pioneered this surgery, it was a group effort. Science is never a single-person endeavor; there’s always a group of us.

J.B.: And now your work is catching on.

Feldman: Yes, and I have another really cool thing to tell you: I just got an email from the biotech company that provides us with stem cells; they say they’ve been approached by Massachusetts General Hospital, which would like to become part of the trial. It’s really gained traction in their ALS clinic.

J.B.: In what way does Phase II go beyond Phase I?

Feldman: With Phase II, we want to find out if the stem cells help improve survival. Can they change respiratory function, especially given that in Phase II we’re doing cervical injections?

J.B.: Will there be a Phase III?

Feldman: (laughs) We certainly hope so; that’s our goal.

J.B.: In my father’s case, it took a while to figure out that he had ALS. The weakness in his left arm and leg was initially misdiagnosed as diabetic neuropathy and stenosis. Finally, he went to the Cleveland Clinic where testing confirmed that he has sporadic ALS. This was reconfirmed at your ALS clinic here at U of M. Do you have any clues as to what causes sporadic ALS?

Feldman: We know more about sporadic ALS than we did before. One very interesting finding is that approximately eight to 10 percent of patients who we believe have sporadic ALS all carry the same gene, but we don’t yet know the function of this gene. I personally believe that there is an environmental component to at least some individuals who have ALS. And I say that based on the fact that there are clusters of ALS cases near Superfund or toxic sites. There are also clusters of ALS in the military, particularly among people who work adjacent to airplanes and their fumes.

Some individuals may be more susceptible to the disorder. There’s a subset of individuals who are young and athletic, like Lou Gehrig was. But why Person A gets it and Person B doesn’t when they’re exposed to exactly the same environmental conditions and have even similar DNA backgrounds, like a brother and sister, we don’t know.

J.B.: You designed an instrument that detects diabetic neuropathy much more rapidly than other tests. What about ALS, which can imitate other maladies? Is there an easy way to detect it?

Feldman: Not yet. ALS can present in so many different ways and while it has one name—this is such an important part of this disease—it contains many different disorders. Your father has a subset of ALS that occurs in men, usually in their sixties, when one arm becomes weak and then the other one becomes weak, as well.

J.B.: Yes. The weakness started in my father’s left arm.

Lou GehrigFeldman: In this subset of ALS patients, they usually retain their ability to speak, swallow and walk. Although sometimes their ability to walk is impaired because they’ve lost use of their arms, which become dead weight. So you can come into my clinic and see a group of men just like this. Seated next to them is a group of two or three women who are at completely normal strength but have lost their ability to speak and swallow, a condition known as “bulbar onset.”

There’s a subgroup of women who have bulbar onset, but retain their strength. They’ll sit there with their pads and write away. Is that the same disease? Probably not. But it carries the same name. This isn’t medical education, so I won’t sit here and give you the other 10 types, but you can understand why a simple screening tool can’t be done for ALS. We try to fast-track everything we’re doing, because it’s such a difficult disorder.

Cooper: When you transplant stem cells, what do those cells do?

Feldman: What we find is, when the stem cells are injected into the spinal cord, they surround the sick motor neurons—the large nerve cells that are in the spinal cord that are dying from Lou Gehrig’s disease—contact them and nurse them back to health.

Cooper: Now you’re moving higher up on the spinal cord.

Feldman: We’ve moved on to what are called the cervical injections, at the very base of the neck where there’s a little bit of a bump—approximately cervical level 5. That’s the area we inject. The large motor neurons in that area supply the nerves that allow you to breathe. We want to preserve those nerves for when the disease progresses and patients develop respiratory dysfunction.

Cooper: Do different stem cells do different things?

Feldman: That’s a great question. We don’t know about that yet in man because we have only injected one type of stem cells: neural progenitor stem cells taken from the spinal cord area of a three-week-old spontaneous abortus. Those cells are hardly developed, but they’re developed enough to know that they want to become some sort of nerve cell. An embryonic cell is what we call totipotent; it can become any type of cell. So those are the kinds of cells we inject.

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And then the spinal cord group in Miami is using another type of cell. I think what’s going to happen is that once the FDA begins to feel more comfortable with cellular therapeutics, which we’re helping them to do, to define what is a good clinical trial in this brand-new arena, what are the precautions, the checks that one must undergo; more people will enter the arena and try lots of different types of cells.

J.B.: This is real tangible hope, in the face of such terrible diseases. Are you moving over into the Alzheimer’s realm with stem cell research?

Feldman: In animals. We’re not there yet with human beings.

J.B.: I wanted to touch on the teaching you do, which is also very important. You’ve had about 40 postdoctoral fellows in your laboratory become neuroscientists. About 36 neurologists have also trained under you.

Feldman: That’s right.

J.B.: And they’ve chosen to specialize in the treatment of neurodegenerative disease, with an emphasis on ALS. It seems that you’re passing down your work to them, ensuring that this critical research is carried on well into the future.

Feldman: Understanding the pathogenesis of disease is a calling for me. I’ve focused my career on the complications of diabetes and also neurodegenerative diseases. Particularly ALS and more recently Alzheimer’s. In my lifetime, I hope to develop a treatment for one or more of these disorders. The more people I train who get excited and involved, the more I extend my sphere of influence. I hope this younger group continues to do the work.

The cool thing is that we have made a lot of interesting discoveries as a group. The more people I train, the more people they train. The better and more educated our scientific and biomedical research workforce is, the more likely we are to achieve real accomplishments. We have the best-educated biomedical research workforce in the world, right here in the US. That’s where our country excels.

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Cooper: As research director of U of M’s ALS Clinic, do you personally work with patients?

Feldman: I do. I see patients 30 percent of the time and do research 70 percent of the time. The fellows that I train and younger junior faculty see my patients along with me. In my science laboratory, I work with my postdoctoral fellows.

J.B.: Do you sleep much?


Cooper: Do you see clients who haven’t been able to get a conclusive diagnosis?

Feldman: Yes, that’s one of my specialties. When people come to see me for a third opinion, hopefully, the buck will stop with me. In fact, that’s what I try to tell most people, that if they’ve waited this long to get an appointment—because our wait time for an appointment is embarrassingly long—that the buck will stop with us and we’ll figure out what’s wrong with them.

Cooper: I’ve interviewed lots of physicians over the years and it’s always great to find one with your passion.

Feldman: Thank you. I really appreciate that.

ALS Association
Taubman Institute
Miami Project

Articles in the Scott Baio Issue; Senator Harkin — Trying to Make it Work; Ashley Fiolek — Kickin’ up Dirt; Humor — Die Laughing; Geri Jewell — Pet Power; Eva Feldman, MD, PhD — ALS and Stem Cell Therapy; Beyond Silence — Deafness in India; Long Haul Paul — Q&A with a PA; Models of Diversity — Embrace it! ; Governor Markell — Blueprint to Employment; China — A Coach with Passion; EMPOWER — Global Inclusion; FREEJ — Grandmothers Rule; MIT — Leveraged Freedom Chair; Scott Baio — Happy Days; MADA — Global Assistive Technology; ABILITY’s Crossword Puzzle; Events and Conferences…subscribe

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