July 31, 2007 

Stem Cell Strategy Shows Challenges for ALS

[Quick Summary: Stem cells engineered to make excess amounts of a helper molecule can aid the survival of sick motor neurons in a rat model, providing hope that new approaches will bring success by combining stem cell and other strategies to ALS.]

Human stem cells engineered to make excess amounts of a helper molecule can aid the survival of sick motor neurons in a rat model of amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease), but the stem cell implants do not preserve the ability of the nerves to contact muscle. The findings by Clive Svendsen, Ph.D., and colleagues at the Waisman Center, University of Wisconsin, Madison, highlight challenges to a stem cell therapy for the disease but also provide clear direction for new approaches that could bring clinical success.

“While this approach represents a unique way to prevent motor neuron loss, our data also suggest that additional strategies may also be required for maintenance of neuromuscular connections and full functional recovery,” the researchers wrote in their report published in the Public Library of Science One journal. Masatoshi Suzuki, Ph.D., at Waisman was the major contributor and the first author of the report.

“However, simply maintaining motor neurons in patients would the first step of a therapeutic advance for this devastating and incurable disease, while future strategies focused on the maintenance of the neuromuscular junction,” the investigators added. Svendsen and colleagues at the University of Wisconsin will pursue added strategies with a new grant from the National Institutes of Health (NIH).

Svendsen said, “The data generated with funding from The ALS Association has provided crucial evidence to the NIH that it will be possible to further explore the role of plasticity, stem cells and growth factors as potential treatments for ALS.  In collaboration with other University of Wisconsin researchers Su-Chun Zhang, M.D., Ph.D., and Gordon Mitchell, Ph.D., this new program grant will provide federal funding for five years of research in this area which we hope will add to the overall goal of understanding why ALS occurs, and how we may be able to treat it." Plasticity refers to the ability of the nervous system to adapt and repair itself after challenges.

Funded primarily by The ALS Association, findings published so far show engineered stem cells can sustain the motor neurons that are dying in the disease. The redesigned stem cells survive after implant and produce a continuous supply of the molecule, glial derived neural growth factor (GDNF).

Rats making a mutant protein, copper-zinc superoxide dismutase (SOD1), serve as a model of the human disease with many of its features. The motor neurons lived longer in those rats given the human stem cell implants making GDNF, but there was no change in the onset of paralysis or the time of survival. In fact the neurons, despite surviving, were not connecting to muscle.

The transplanted stem cells remain as immature progenitors, neither neuron nor glial cell, yet making the protective GDNF, the action apparently crucial to the longer survival of the motor neurons. They were not acting as glial cells, which are known to provide support for neighboring nerve cells. They did not alter the glial inflammatory reaction that is part of the ALS disease process. Nor were they affecting the balance of the nerve cell messenger, glutamate, implicated in ALS.

Aside from ruling out these actions, the researchers carefully controlled for factors such as variations in overall survival time among the rats and sex differences: male rats appear to be more sensitive to the disease, as is the case for people with ALS.

Thus the investigators have dissected away various molecular aspects of the disease to focus on the critical fact that a supply of the correct molecule can allow survival of nerve cells despite a disease environment. The next step toward using stem cells to treat ALS will have to capitalize on this new knowledge bringing in other strategies to allow the nerve muscle junction to remain intact and perhaps using molecules known to encourage nerve fibers to extend to muscle.

The Wisconsin Chapter of The ALS Association funded this research.

Refer to The ALS Association’s web site under the research tab for further information about stem cells and cell targets in ALS.

The full research report is available at http://www.plosone.org/doi/pone.0000689.