Discovering Small Molecules to Rescue SOD-1 folding

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease characterized by selective loss of motor neurons and atrophy of skeletal muscle. ALS is the most common motor neuron disease in the adult population, affecting 30,000 in the United States alone. Approximately 15% to 20% of familial ALS cases are associated with dominant missense mutations in the Cu/Zn superoxide dismutase 1 (SOD1) gene. A pathologic feature of both sporadic and familial ALS is the accumulation of potentially toxic proteinaceous inclusions containing misfolded SOD1 in the cytosol of degenerating neurons. A series of recent studies strongly suggest that ALS results from a gain of toxic function, which arises either during early steps of inclusion formation or from the inclusions themselves. In this regard, the discovery of compounds that affect SOD1 misfolding would be a major step toward the development of drugs for the treatment and prevention of ALS. To date however, the search for such compounds has been hindered by a lack of appropriate high-throughput screening (HTS) methods. Reata Discovery, Inc., the applicant organization, has obtained an exclusive license to a novel, proprietary cell-based HTS method that directly monitors SOD1 folding and solubility in live cells. Using this method, we have established a tight correlation between reporter signal and the published effects of disease-associated mutations on the stability of SOD1. Notably, this system is sensitive and has excellent dynamic range in mammalian cells, providing up to a 50-fold difference in signal between wild type SOD1 and the most severe mutations. Based upon this robust assay, Reata has initiated a program to identify small drug-like compounds that impact SOD1 misfolding. The proposed funding will significantly enhance this effort by expanding the scope of compound libraries and supplementing internal funds that Reata has already committed to the program.