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

描述（由申请方提供）：脊髓延髓肌萎缩症（SBMA或肯尼迪病）是一种罕见的遗传性神经退行性疾病，影响下运动神经元，伴有进行性肌肉萎缩和延髓、面部和四肢肌肉无力，导致受影响男性出现进行性言语障碍和运动功能障碍。目前没有有效的治疗方法。SBMA是由X染色体连锁的雄激素受体（AR）基因突变引起的，导致氨基酸谷氨酰胺（polyQ）的过度重复。由这些扩展的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，包括突变体polyQ AR。已经显示腹膜内（IP）施用的化合物之一阿索J 9改善SBMA表现并改善体内SBMA转基因小鼠模型中的存活率和性功能。在这个项目中，我们建议将ASC-J 9（或更有效的类似物）开发成男性SBMA的口服治疗药物。该授权的目的将是首先证明口服施用ASC-J 9（或类似物）在SBMA转基因小鼠模型中是有效的，类似于或上级于当腹腔内施用ASC-J 9时在SBMA小鼠中的观察结果。所选化合物（ASC J 9或类似物）的口服制剂适于每日口服给药于人（例如，胶囊剂、片剂、糖浆剂）。还将对所选化合物进行临床前毒理学、安全药理学和ADME研究，以支持IND申报和临床研究的启动。影响：使用ASC-J 9（或类似物）开发口服治疗剂代表了用于治疗SBMA患者的新颖且有前景的方法，SBMA患者是这种疾病中显著未满足的医疗需求，没有有效的治疗方法。 公共卫生相关性：SBMA是一种由雄激素受体（AR）基因突变引起的神经肌肉疾病。目前，没有治疗方法可以减轻症状或改变SBMA疾病的病程。ASC-J 9是一种诱导AR降解的化合物，在转基因小鼠中表现出功效并改善SBMA表型，因此代表了可用于开发成SBMA治疗性治疗的有前景的候选药物。

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.