Feldman, MD and PhD, works closely with her research team to seek
cures for some of the worlds most devastating diseases, including
Alzheimers, diabetic neuropathy and amyotrophic lateral sclerosis
(ALS), which is often called Lou Gehrigs 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
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, ABILITYs 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, weve 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 partthe 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.
Weve 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. [Editors Note: Not long after this
interview, Phase II was approved by the FDA in a process where Feldmans
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: Its definitely surgery: We expose the spinal cord,
taking away the bone and peeling back the cords other coverings.
Then we take this very thin needle and put it into the spinal cord
to inject the stem cells.
Cooper: This isnt what youd call minimally-invasive
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
whats known as a hematoma and then youd get a lot of blood.
So unfortunately we cant do a minimally invasive procedure with
this type of surgery. Now, I will tell you that were working
with our bioengineers here to address this, because we would prefer
to do a less invasive procedure. Currently we are at the development
J.B.: How far off is Phase II?
Feldman: If all goes well, we should be operating by the summertime.
J.B.: Oh, thats great.
Feldman: Yes, we submitted a protocol to the FDA that theyd
never seen before, so its been challenging for them and with
that challenge comes the opportunity to set new standards for cellular
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
Feldman: Michigan was one of a handful of states where it was still
illegal to create embryonic stem cell lineseven 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 namedand which
I runpersonally 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 were 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 Huntingtons 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 youre implementing in Phase II?
Feldman: No, a group of researchers in Italy who observed our surgery
at Emory have begun a trial. Theyre 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 were 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.
J.B.: Lets 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 Gehrigs 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
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;
theres 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 theyve been approached by Massachusetts General
Hospital, which would like to become part of the trial. Its
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 were doing cervical injections?
J.B.: Will there be a Phase III?
Feldman: (laughs) We certainly hope so; thats our goal.
J.B.: In my fathers 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 dont
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. Theres
a subset of individuals who are young and athletic, like Lou Gehrig
was. But why Person A gets it and Person B doesnt when theyre
exposed to exactly the same environmental conditions and have even
similar DNA backgrounds, like a brother and sister, we dont
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 namethis is such an important part of this diseaseit
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 fathers left arm.
Feldman: 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 theyve 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.
Theres a subgroup of women who have bulbar onset, but retain
their strength. Theyll sit there with their pads and write away.
Is that the same disease? Probably not. But it carries the same name.
This isnt medical education, so I wont sit here and give
you the other 10 types, but you can understand why a simple screening
tool cant be done for ALS. We try to fast-track everything were
doing, because its 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 neuronsthe large nerve
cells that are in the spinal cord that are dying from Lou Gehrigs
diseasecontact them and nurse them back to health.
Cooper: Now youre moving higher up on the spinal cord.
Feldman: Weve moved on to what are called the cervical injections,
at the very base of the neck where theres a little bit of a
bumpapproximately cervical level 5. Thats 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: Thats a great question. We dont 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 theyre
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.
And then the spinal cord group in Miami is using another type of cell.
I think whats going to happen is that once the FDA begins to
feel more comfortable with cellular therapeutics, which were
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 Alzheimers realm with
stem cell research?
Feldman: In animals. Were not there yet with human beings.
J.B.: I wanted to touch on the teaching you do, which is also very
important. Youve had about 40 postdoctoral fellows in your laboratory
become neuroscientists. About 36 neurologists have also trained under
Feldman: Thats right.
J.B.: And theyve chosen to specialize in the treatment of neurodegenerative
disease, with an emphasis on ALS. It seems that youre 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. Ive focused my career on the complications of diabetes and
also neurodegenerative diseases. Particularly ALS and more recently
Alzheimers. 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. Thats where our country excels.....
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