DESCRIPTION (provided by applicant): Spinal and bulbar muscular atrophy (SBMA or Kennedy's Disease) is a rare hereditary neurodegenerative disease that affects lower motor neurons, with progressive muscle atrophy and weakness of the bulbar, facial, and limb muscles, resulting in progressive dysphasia and motor dysfunction in affected men. No effective therapy currently exists. SBMA is caused by an X-chromosome linked androgen receptor (AR) gene mutation resulting in excessive repeats of the amino acid glutamine (polyQ). Neurotoxicity caused by these expanded polyQ AR aggregates is believed to play a pivotal role in the pathogenesis of SBMA. Recently, we discovered a group of small molecule compounds that selectively induces degradation of AR protein, including mutant polyQ AR, in vitro. One of the compounds, ASO J9, administered intraperitoneally (IP) has already been shown to ameliorate SBMA manifestations and to improve survival and sexual function in an in vivo SBMA transgenic mouse model. In this project we propose to develop ASC-J9 (or a more potent analog) into an oral therapeutic treatment for SBMA in men. The goals of this grant will be to first demonstrate that orally administered ASC-J9 (or an analog) is efficacious in the SBMA transgenic mouse model similar or superior to the observations in SBMA mice when ASC-J9 was administered intraperitoneally. An oral formulation of the selected compound (ASC J9 or analog) suitable for daily oral administration to humans (e.g., capsules, tablets, syrup) will be developed. Preclinical toxicology, safety pharmacology, and ADME studies will also be performed for the selected compound to support IND filing and the initiation of clinical studies. IMPACT: Using ASC-J9 (or an analog) to develop an oral therapeutic represents a novel and promising approach for the treatment of SBMA patients, a significant unmet medical need in this disease with no effective treatment available.

PUBLIC HEALTH RELEVANCE: SBMA is a neuromuscular disease caused by mutant androgen receptor (AR) gene. Currently, no treatment is available to abate the symptoms or alter the course of SBMA disease. ASC-J9 is a compound that induces AR degradation, exhibits efficacy and ameliorates SBMA phenotype in transgenic mice, thus representing a promising drug candidate available for developing into a therapeutic treatment for SBMA.