Kailee Small

November 25, 2014

Grand Rounds: Intraspinal Stem Cell Transplantation
On November 14, 2014, Dr. Eva Feldman delivered a Grand Rounds presentation
entitled, Intraspinal Stem Cell Transplantation: Results of the Phase 1 Clinical Trial," at the
University of Texas Science Center in Houston, TX. She shared her experiences developing
FDA-approved clinical trials that tested the effects of surgical transplantation of stem cells into
the spinal cord of patients suffering from amyotrophic lateral sclerosis. The objectives of her
presentation were to describe the extensive process required for FDA approval of human
research and to explain the results of her Phase I trial on stem cell injections administered to
ALS patients.
Dr. Feldman designed her trial according to a cellular approach that was based on the
underlying idea that stem cells would provide neural protection in neurodegenerative diseases by
forming synapses, producing growth factors, and blocking inflammation. She began her line of
research by conducting a pre-clinical animal trial using a rat model of ALS. The goal of the
experiment was to implant stem cells in areas of ALS-induced cell death to see if they would
have an effect on the prognosis of the rat. Dr. Feldman originally used embryonic stem cells
because their totipotent nature allows them to differentiate into any type of cell in the body.
Initially, there was clear increase in animal function as the rats became more robust and lived
longer, but 10% of rats became paralyzed quicker than they should have with ALS. Because the
totipotent embryonic stem cells had the potential to differentiate into any type of cell, they grew
into tumors in 10% of the rats. For this reason, Dr. Feldman decided to use neural progenitor
cells because they are further along in the differentiation process than embryonic stem cells, and
their multipotent nature allows them to turn into an type of nerve cell or glial cell, including
astrocytes and oligodendrocytes. After surgically implanting the stem cells into the ventral horn

of the rats spinal cord, Dr. Feldman observed that about half of the cells became nerve cells and
half became glia or progenitor cells. All of them were well incorporated into the normal spinal
cord environment without producing any tumors. The cells did not migrate out of the area and
project to muscle, as Dr. Feldman had originally anticipated. However, they preserved motor
neuron function by surrounding the sick motor neurons that were in the process of degenerating
and forming synaptic contacts with them, thus providing them with neural protection. The neural
protective role of the stem cells in the rats spinal cord allowed their large motor neurons to
survive, resulting in the ability to live longer while still maintaining functional muscle control.
Following the success of the pre-clinical rat trial, Dr. Feldman conducted a large animal
study using mini-pigs in order to qualify for FDA approval to transplant stem cells into human
subjects. Once she received approval, she began her 1 safety trial, which consisted of 18
surgeries performed on 15 ALS patients. The first nine subjects received stem cell transplants in
the lumbar spinal cord, while the remaining three subjects received transplants in the cervical
spinal cord. After the cervical cord procedure was proven to be safe, three people from the
lumbar group were asked to return to undergo an additional stem cell transplant in the cervical
cord. Up to 100,000 cells were implanted at a time and each participant received up to 1.5
million cells in total. They were tolerated well with no side effects (Feldman et al., 2014). Due to
success of the Phase I trial, the FDA approved a Phase II trial that will focus on injections of up
to 400,000 stem cells at a time into the cervical spinal cord to continue the safety assessment,
and to see if this procedure provides possible benefits for patients with ALS. Participants will
receive up to 16 million cells in total (Neuralstem, 2014). Based on her results thus far, Dr.
Feldman expects that when the stem cells are transplanted into the human spinal cord of ALS
patients, they will synapse with the patients motor neurons and provide neural protection from

the rapid degeneration that normally characterizes ALS (E.L. Feldman, personal communication,
November 14, 2014).
Amyotrophic lateral sclerosis (ALS), or Lou Gehrigs disease, is a rapidly progressing
neurological disease that attacks motor neurons controlling voluntary muscles, eventually
causing death due to respiratory failure. Both upper motor neurons (in the brain) and lower motor
neurons (in the brainstem and spinal cord) degenerate and die, therefore eliminating signal
transmission to the muscles. Without intact signaling, muscles start to weaken and atrophy and
the patient starts to experiences fasciculations. Once the diaphragm can no longer function, the
patient becomes dependent upon a ventilator to breathe (National Institute of Mental Health
[NIMH], 2013). On average, ALS is diagnosed in susceptible patients around 55 years of age,
but the disease affects younger and older people as well. Most people with ALS die within 3-5
years due to respiratory failure after their diaphragm muscles can no longer maintain adequate
respiration (National Library of Medicine [NLM], 2012).
Symptoms of ALS include muscle weakness in one or more hands, arms, legs or muscles
used in speech, swallowing, or breathing, fasciculation and cramping of the muscles in the hands
and feet, thick speech with a difficulty projecting the voice, impaired use of the arms and legs,
and in more advanced stages, shortness of breath, difficulty in breathing and swallowing. The
symptoms present themselves so subtly that they are often overlooked. Muscle weakness is the
hallmark of ALS, and may present itself as sudden tripping, dropping things, abnormal fatigue of
the limbs, slurred speech, muscle cramps and twitches and/or uncontrollable periods of laughing
and crying; however, its presentation varies in different people. Muscle weakness usually starts
at the legs or arms/hands and spreads towards the trunk, eventually making it difficult to speak
(dysarthria), swallow (dysphagia), chew and breathe. ALS only attacks motor neurons, meaning
that sight, touch, hearing, taste and smell are unaffected. Upper motor neuron involvement can

be seen in tight, stiff muscles (hyperreflexia) and Babinskis sign, while symptoms of lower
motor neuron involvement include muscle weakness, atrophy and fasciculations (NIMH, 2013).
Dr. Feldmans focus on the neural protective effects of stem cell implantation on patients
with ALS is based upon the typical presentation of ALS in humans. The eventual goal of
conducting trials such as these is to create a cell therapy that can help patients suffering from the
typical symptoms of ALS to preserve motor function as long as possible, delaying the
progression of the disease and to increase the lifespan. Dr. Feldman hopes that developments in
this area will contribute to treatments for all types of neurodegenerative diseases (E.L. Feldman,
personal communication, November 14, 2014).

References
Feldman, E. L. (November 14, 2014). Intraspinal Stem Cell Transplantation: Results of the Phase
1 Clinical Trial." 26th Annual William S. Fields Lecture. Lecture conducted from
Department of Neurology at University of Texas Health Science Center, Houston, TX.
Feldman, E. L., Boulis, N. M., Hur, J., Johe, K., Rutkove, S. B., Federici, T., Polak, M., Bordeau,
J., Sakowski, S. A., Glass, J.D. Intraspinal neural stem cell transplantation in
amyotrophic lateral sclerosis: phase 1 trial outcomes. Ann Neurol 2014;75:363373.
National Library of Medicine. (2012). Amyotrophic lateral sclerosis. Retrieved from
http://www.nlm.nih.gov/medlineplus/ency/article/000688.htm
National Institute of Neurological Disorders and Stroke. (2013). Amyotrophic lateral
sclerosis (ALS) fact sheet. (NIH Publication No. 13-916). Retrieved from
http://www.ninds.nih.gov/disorders/amyotrophiclateralsclerosis/detail_als.htm
Neuralstem. (2014). Neuralstem cell therapy for ALS. Retrieved from
http://www.neuralstem.com/cell-therapy-for-als