ALS Association Funds HSCI Motor Neuron Screening Program
With support from the ALS Association's TREAT ALS translational research initiative, the Harvard Stem Cell Institute's new Therapeutic Screening Center is working to develop new techniques to screen small molecule candidates that might eventually be developed into drugs to slow or halt the progress of amyotrophic lateral sclerosis, commonly known as Lou Gehrig's disease.
Lee Rubin, Ph.D., director of the HSCI Therapeutic Screening Center called the ALS Association initiative "a major step forward for us as we work to move embryonic stem cell findings through the translational process from basic discovery to forms that may eventually help patients."
The ALS screening program will harness motor neurons derived from mouse embryonic stem cells and will draw on the work of HSCI Principal Faculty Member Kevin Eggan, whose lab will generate the cells.
Speaking of Rubin and Eggan's collaborative effort, Lucie Bruijn, Ph.D., science director and vice president of The ALS Association said "these are significant players who have proven success in finding potential therapeutics for another motor neuron disease," said. "We are encouraged to have their expertise applied to the search for effective ALS treatments in actual motor neurons."
TREAT ALS (Translational Research Advancing Therapy for ALS) is a drug discovery program and clinical trials process that accelerates discovery and testing of new treatments for the disease. The project to develop and validate this cell based screening assay is milestone driven and will depend on reaching set goals for continued funding.
Motor neurons are the cells that die in the disease, but historically have been challenging to obtain and grow in the lab. It has been difficult to create an optimal automated screening assay aimed at candidate discovery for ALS. Standard tissue culture demands thousands of labor intensive dissections of mouse spinal cords to provide the targeted cells in sufficient numbers. New techniques now can generate billions of mouse motor neurons per week.
The investigators also can provide mouse motor neurons that carry a mutation involved in some inherited forms of the disease. To do so, they will obtain stem cells from mice expressing the human mutant protein, copper-zinc superoxide dismutase (SOD1).
This SOD1 mutation expressed in motor neurons might influence how the cells respond to challenges in lab dishes. If any small molecule turns out to allow these mutant motor neurons to survive less than optimal growing conditions, it might be doing so in a way that corrects the disease situation and could point the way to effective treatment.
Two different challenges for the growing motor neurons will be validated with initial TREAT ALS funding; one is withdrawal of growth factors; the other is to produce excess stimulation with a compound that mimics the messenger molecule, glutamate. Both challenges are suspect in the ALS disease process.
Once the screening assay is optimized for one or both challenges, the researchers will test thousands of small molecules to rapidly identify by robotics any that could serve as a potential ALS therapy. Positive "hits" in the assays would have to be retested and confirmed, then optimized chemically as a potential drug candidate. Animal testing would be a further prerequisite to any clinical investigation.
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