Novel Therapeutic Agents for ALS

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. The worldwide prevalence of ALS is estimated at ~87,000 patients, in part due to the low median survival of 3 to 5 years post diagnosis. Riluzole is the sole drug currently approved for the treatment of ALS and only extends the survival of ALS patients by 2-3 months. The lack of therapeutics for ALS treatment is in part due to poorly described disease etiology. Four hypotheses have been advanced to explain the basis for ALS: glutamate excitotoxicity, impaired mitochondrial function, oxidative stress and aberrant protein aggregation. We are focusing our efforts on testing the latter hypothesis because pathology studies consistently indicate that aberrant protein aggregation is a cardinal feature of the clinical disease. The overall goal of this project is to identify small molecule compounds that block or reverse SOD1-based protein mis-folding or the toxic effects thereof, and to evaluate these compounds as potential therapeutic candidates for ALS. This project is a collaboration between Cambria Biosciences and the laboratory of Rick Morimoto (Northwestern University). Scientists at Cambria have extensive experience in implementing high-throughput drug discovery screens. Dr. Morimoto is a leading expert in the field of protein dynamics and homeostasis. Thus this collaboration brings together a unique combination of strengths. In the proposed SBIR Phase I timeframe, we will pursue two complementary high- throughput screens and evaluation of identified active compounds, as outlined in the following specific aims: (1) Identify compounds that block or reverse the toxic effects of protein aggregates employing an established high-throughput cell protection screen based on the toxic effects of G93A mutant SOD1 expression in PC12 cells. (2) Identify compounds that block or reverse the formation of protein aggregates utilizing an operational high content screen employing PC12 cells expressing G85R mutant SOD1-YFP and in which protein aggregation can be directly observed and quantified. (3) Select an elite set of compounds to be evaluated as therapeutic candidates in Phase II. Confirmed actives from the primary screens will be evaluated for efficacy and potency via dose response assays and tested for their effect on chaperone induction, the enhancement of proteasome activity and spectrum of activity against a panel of mis- folded proteins (SOD1, polyQ huntingtin, tau, amyloid Aa, and prion proteins). In Phase II compounds with the highest efficacy, potency, spectrum and selectivity will be optimized and tested in animal ALS models. Amyotrophic lateral sclerosis, also called ALS and Lou Gehrig's disease, affects ~87,000 patients worldwide with about one third of these patients residing in the United States. ALS patients generally survive only 3 to 5 years following the onset of the disease. Riluzole, the sole currently clinically approved medication for ALS, only extends patient survival by 2-3 months. We propose to identify potential new medicines that will suppress or reverse the underlying disease process in ALS, and as a result improve the health and lifespan of people with this disease.