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: 8252177
• 负责人: CHARLES C-Y SHIH
• 金额: --
• 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/8252177
• 关键词: ADME Study; Abate; Adverse effects; Affect; Age; Amino Acids; Amyotrophic Lateral Sclerosis; Androgen Antagonists; Androgen Receptor; Androgens; Animals; Biological Availability; Brain Stem; CAG repeat; Cells; Cessation of life; Chronic; Clinical Research; Clinical Trials; Code; Degenerative Disorder; Deglutition; Development; Diagnosis; Disease; Drug Formulations; Dysphasia; Exhibits; Face; Functional disorder; Gene Mutation; Glutamine; Goals; Grant; Hand; Human; In Vitro; Insulin-Like Growth Factor I; Investigational Drugs; Kennedy Syndrome; Lead; Life; Limb structure; Link; Medical; Molecular; Molecular Chaperones; Motor; Motor Neurons; Mus; Muscle; Muscle Cramp; Muscle Weakness; Muscle fasciculation; Muscular Atrophy; Nerve Degeneration; Nervous System Heredodegenerative Disorders; Neuraxis; Neuromuscular Diseases; Neurons; Nuclear Receptors; Nucleotides; Oral; Oral Administration; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phenotype; Phosphorylation; Play; Population; Receptor Gene; Reporting; Respiratory Tract Infections; Role; Safety; Severity of illness; Sex Functioning; Speech; Spinal; Staging; Stanolone; Symptoms; Tablets; Testosterone; Therapeutic; Tongue; Toxicology; Transgenic Mice; Transgenic Organisms; Tremor; Woman; X Chromosome; analog; base; capsule; deprivation; drug candidate; effective therapy; experience; healthy volunteer; improved; in vivo; men; mouse model; mutant; neurotoxicity; novel; novel therapeutics; polyglutamine; pre-clinical; preclinical study; programs; protein degradation; public health relevance; receptor; safety study; small molecule; spinal and bulbar muscular atrophy; wasting

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.

描述（由申请人提供）：脊柱和鳞茎肌肉萎缩（SBMA或肯尼迪氏病）是一种罕见的遗传神经退行性疾病，会影响较低的运动神经元，进行性肌肉萎缩，面部，面部和lim肌的萎缩，lim肌和lim肌肌肉，导致渐进的失调和运动障碍和运动障碍，导致Adycred ernded ernded Mercy。目前没有有效的疗法。 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在SBMA的发病机理中起关键作用。最近，我们在体外发现了一组小分子化合物，这些化合物有选择地诱导AR蛋白的降解，包括突变体PolyQ AR，体外。其中一种化合物ASO J9在体内SBMA转基因小鼠模型中已经显示出腹膜内（IP）的腹膜内（IP）来改善SBMA表现并提高生存和性功能。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。该赠款的目标是首先证明口服ASC-J9（或类似物）在SBMA转基因小鼠模型中有效或与SBMA小鼠的观测值相似或优于SBMA小鼠时，当ASC-J9被内积进行腹膜内。将开发适合每日口服人类（例如胶囊，片剂，糖浆）的选定化合物（ASC J9或类似物）的口服配方。临床前毒理学，安全药理学和ADME研究也将用于所选化合物，以支持IND归档和临床研究的启动。影响：使用ASC-J9（或类似物）开发口服治疗方法代表了一种新颖而有希望的治疗SBMA患者的方法，这是该疾病的重要医疗需求，没有有效的治疗。