Neuroprotective Small Molecules for the Treatment of Amyotrophic Lateral Sclerosis (ALS)
Posted December 4, 2009
Serge Przedborski, Ph.D., Columbia University, New York

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a progressive neurodegenerative disease characterized by the gradual degeneration and death of motor neurons in the brain and spinal cord. In the United States, 5,000 people are estimated to get diagnosed with ALS annually. Furthermore, U.S. military veterans reportedly have a higher risk of developing ALS. Approximately 90 to 95 percent of ALS cases are sporadic with no apparent risk factor, whereas 5 to 10 percent of ALS cases are hereditary and are known as familial ALS. Mutations in the gene encoding superoxide dismutase (SOD1), a potent antioxidant enzyme, are reportedly associated with about 20 percent of familial ALS cases. Dr. Serge Przedborski from Columbia University previously reported in vitro studies indicating that rodent astrocytes (non-neuronal cells surrounding neurons) expressing mutant SOD1 contribute to a more severe form of neurodegenerative process by killing spinal primary motor neurons and embryonic stem cell-derived motor neurons (ES-MNs). The death of motor neurons is accomplished through soluble neurotoxic factors mimicking the ALS phenotype compared to mutated SOD1 expression in primary motor neurons alone. Dr. Przedborski received a 2007 ALS Research Program Therapeutic Development Award to identify small molecule- neuroprotective agents for treatment of ALS. Dr. Przedborski along with collaborators Drs. Stockwell and Henderson at Columbia and Dr. Rubin at Harvard performed high-throughput screening of libraries of small compounds (about 30,000 small molecules at Columbia and 50,000 molecules at Harvard) to examine the individual effect at 10 µM concentration on the survival of mutant mouse ES-MNs cultured with rodent astrocytes expressing mutant SOD1. Promising compounds with high rates of ES-MNs survival were validated at both institutions, and were further tested at 10 different concentrations from 1 nM to 30 µM. After a comprehensive primary screening, 100 confirmed protective compounds were selected for secondary screening in the Przedborski laboratory using both rodent or mouse SOD1 mutant astrocytes and a mouse primary motor neuron model to study not only motor neuron survival rate but also neuronal protection of soma and processes by an assessment of axonal length. Translational potential of this on-going research is high. It should result in the identification of twenty most promising compounds with the highest potency, efficacy, and relevance to humans, which will move forward for pre-clinical and clinical studies that ultimately may result in a therapy for people living with ALS.

Selected Publications:

Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice
Banerjee R, Mosley RL, Reynolds AD, Dhar A, Jackson-Lewis V, Gordon PH, Przedborski S, Gendelman HE.
PLoS One. 2008 Jul 23;3(7):e2740.

Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons
Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S.
Nat Neurosci. 2007 May;10(5):615-22. Epub 2007 Apr 15.

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