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

描述(申请人提供)：脊柱和延髓肌肉萎缩症(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，导致受累男性进行性语言障碍和运动功能障碍。目前还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。这些扩展的多Q AR聚集体引起的神经毒性被认为在SBMA的发病机制中发挥了关键作用。最近，我们在体外发现了一组选择性地诱导AR蛋白降解的小分子化合物，包括突变体PolyQ AR。其中一种化合物ASO J9，在体内SBMA转基因小鼠模型中，已经被证明可以改善SBMA表现，改善存活和性功能。在这个项目中，我们建议将ASC-J9(或更有效的类似物)开发为治疗男性SBMA的口服疗法。这笔赠款的目标将是首先证明口服ASC-J9(或类似物)在SBMA转基因小鼠模型中的有效性，类似于或优于在SBMA小鼠中观察到的ASC-J9经腹膜注射的效果。将开发适合于人类日常口服的所选化合物(ASC J9或类似物)的口服配方(例如胶囊、片剂、糖浆)。还将对选定的化合物进行临床前毒理学、安全性药理学和ADME研究，以支持IND申报和临床研究的启动。影响：使用ASC-J9(或类似物)开发一种口服疗法，代表了治疗SBMA患者的一种新的、有前途的方法，这是这种疾病的一个重大未得到满足的医疗需求，目前还没有有效的治疗方法。

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.