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

脊髓和延髓肌萎缩症口服治疗药物的开发

• 批准号: 8041399
• 负责人: CHARLES C-Y SHIH
• 金额: $ 86.22万
• 依托单位: ANDROSCIENCE CORPORATION
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8041399
• 关键词: ADME Study; Abate; Affect; Amino Acids; Androgen Receptor; Animals; Biological Availability; Chronic; Clinical Research; Clinical Trials; Development; Disease; Drug Formulations; Dysphasia; Exhibits; Face; Functional disorder; Gene Mutation; Glutamine; Goals; Grant; Human; In Vitro; Kennedy Syndrome; Lead; Limb structure; Link; Medical; Motor; Motor Neurons; Mus; Muscle; Muscle Weakness; Muscular Atrophy; Nervous System Heredodegenerative Disorders; Neuromuscular Diseases; Oral; Oral Administration; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Play; Principal Investigator; Receptor Gene; Role; Safety; Sex Functioning; Symptoms; Tablets; Therapeutic; Toxicology; Transgenic Mice; Transgenic Organisms; X Chromosome; analog; capsule; drug candidate; effective therapy; healthy volunteer; improved; in vivo; men; mouse model; mutant; neurotoxicity; novel; polyglutamine; pre-clinical; preclinical study; receptor; safety study; small molecule; spinal and bulbar muscular atrophy

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.

描述（由申请人提供）：脊髓和延髓肌萎缩症（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，导致进行性语言障碍以及受影响男性的运动功能障碍。目前尚无有效的治疗方法。 SBMA 是由 X 染色体连接的雄激素受体 (AR) 基因突变引起的，导致氨基酸谷氨酰胺 (polyQ) 过度重复。这些扩展的polyQ AR聚集体引起的神经毒性被认为在SBMA的发病机制中发挥着关键作用。最近，我们发现了一组在体外选择性诱导AR蛋白降解的小分子化合物，包括突变的polyQ AR。其中一种化合物 ASO J9，腹膜内 (IP) 给药已被证明可以改善 SBMA 表现并改善体内 SBMA 转基因小鼠模型的存活率和性功能。在这个项目中，我们建议将 ASC-J9（或更有效的类似物）开发为男性 SBMA 的口服治疗方法。该资助的目标是首先证明口服 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腹膜内施用 ASC-J9 时在 SBMA 小鼠中观察到的结果。将开发适合人类每日口服给药的所选化合物（ASC J9 或类似物）的口服制剂（例如胶囊、片剂、糖浆）。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 备案和临床研究的启动。影响：使用 ASC-J9（或类似物）开发口服疗法代表了治疗 SBMA 患者的一种新颖且有前途的方法，这种疾病是一种未得到满足的重大医疗需求，且尚无有效的治疗方法。 公共卫生相关性：SBMA 是一种由突变雄激素受体 (AR) 基因引起的神经肌肉疾病。目前，尚无治疗方法可以减轻 SBMA 的症状或改变其病程。 ASC-J9 是一种在转基因小鼠中诱导 AR 降解、表现出功效并改善 SBMA 表型的化合物，因此代表了一种有前途的候选药物，可用于开发成 SBMA 的治疗方法。