Development of an Oral Therapeutic Drug for Spinal and Bulbar Muscular Atrophy

描述（由申请人提供）：脊髓和球肌萎缩症（SBMA或肯尼迪氏病）是一种罕见的遗传性神经退行性疾病，影响下部运动神经元，伴有进行性肌肉萎缩和球、面部和肢体肌肉无力，导致患者进行性吞咽障碍和运动功能障碍。目前尚无有效的治疗方法。SBMA是由x染色体连接雄激素受体（AR）基因突变导致氨基酸谷氨酰胺（polyQ）过量重复引起的。这些扩大的polyQ AR聚集体引起的神经毒性被认为在SBMA的发病机制中起关键作用。最近，我们在体外发现了一组选择性诱导AR蛋白降解的小分子化合物，包括突变型polyQ AR。在体内SBMA转基因小鼠模型中，经腹腔注射的化合物ASO J9已被证明可以改善SBMA的表现，并提高存活率和性功能。在这个项目中，我们建议将ASC-J9（或更有效的类似物）开发成男性SBMA的口服治疗药物。这项资助的目的是首先证明口服ASC-J9（或类似物）在SBMA转基因小鼠模型中是有效的，类似于或优于腹腔给药ASC-J9在SBMA小鼠中的观察结果。所选化合物（ASC J9或类似物）的一种口服制剂将被开发，适用于人类日常口服给药（例如胶囊、片剂、糖浆）。所选化合物的临床前毒理学、安全药理学和ADME研究也将进行，以支持IND申请和临床研究的启动。影响：使用ASC-J9（或类似物）开发一种口服治疗方法代表了治疗SBMA患者的一种新颖而有前途的方法，这是该疾病未满足的重要医疗需求，目前尚无有效治疗方法。

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.