RNAi Therapy for Spinocerebellar Ataxia Type 1

RNAi 疗法治疗 1 型脊髓小脑共济失调

• 批准号: 9479304
• 负责人: Beverly L. Davidson
• 金额: $ 154.87万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9479304
• 关键词: Adult; Affect; Area; Biodistribution; Biological; Brain; Brain Stem; Cerebellar Ataxia; Cerebellum; Clinical; Clinical Trials; Clinical/Radiologic; Disease; Disease model; Dose; Engineering; Genetic Transcription; Human; In Vitro; Inherited; Lead; Macaca mulatta; Measures; Mediating; Messenger RNA; MicroRNAs; Motor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Patients; Pediatric Hospitals; Phase; Phase I Clinical Trials; Phenotype; Philadelphia; Process; Production; Protocols documentation; RNA Interference; RNA Interference Therapy; Regimen; Reporter Genes; Rodent; Route; Safety; Series; Spinocerebellar Ataxias; Testing; Therapeutic; Toxicology; Transgenic Mice; Type 1 Spinocerebellar Ataxia; Viral; Work; ataxin-1; comparative; design; effective therapy; human subject; improved; in vivo; meetings; mouse model; neuropathology; nonhuman primate; polyglutamine; potency testing; pre-clinical; preclinical study; primary endpoint; programs; public health relevance; secondary endpoint; treatment strategy; vector

DESCRIPTION (provided by applicant): Spinocerebellar ataxia type 1 (SCA1) is one of nine polyglutamine expansion diseases and is characterized by cerebellar ataxia and neuronal degeneration in the cerebellum and brainstem. Currently, there are no effective treatment strategies for this disease. Previously, we showed that RNA interference (RNAi)-mediated silencing of ataxin-1 mRNA provides therapeutic benefit in mouse models of SCA1. Adeno-associated viral (AAV) delivery of an engineered microRNA (miRNA) targeting ataxin-1 to the cerebellum of well-established SCA1 transgenic mouse models improved motor phenotypes, neuropathology, and transcriptional changes. We now propose to move our lead vector forward by completing a series of milestones that will lead us to a Phase 1 clinical trial in human subjects. In the UH2 phase of this application we will 1) perform comparability testing of the proposed vector in nonhuman primates to confirm our proposed dosing regimen, and 2) hold a Pre-IND Type B meeting with the CBER of the FDA to receive input on the design of the planned GLP tox study and the proposed Phase 1 protocol. In the UH3 phase of this application we will 1) produce GMP- process comparable vector (GLP vector), 2) perform the planned GLP pharm/tox study in nonhuman primates and rodents, 3) produce GMP-grade vector, 4) prepare and file the IND with the FDA, and 5) perform a phase I/II clinical trial in SCA1 subjects.

描述（申请人提供）：脊髓小脑共济失调1型（SCA1）是九种多聚谷氨酰胺扩张疾病之一，其特征是小脑共济失调以及小脑和脑干中的神经元变性。目前，该疾病尚无有效的治疗策略。此前，我们表明 RNA 干扰 (RNAi) 介导的 ataxin-1 mRNA 沉默可为 SCA1 小鼠模型提供治疗益处。腺相关病毒 (AAV) 将靶向 ataxin-1 的工程化 microRNA (miRNA) 递送至成熟的 SCA1 转基因小鼠模型的小脑，改善了运动表型、神经病理学和转录变化。我们现在建议通过完成一系列里程碑来推动我们的主导向量向前发展，这些里程碑将引导我们进入人类受试者的一期临床试验。在本申请的 UH2 阶段，我们将 1) 在非人类灵长类动物中对提议的载体进行可比性测试，以确认我们提议的给药方案，以及 2) 与 FDA 的 CBER 举行预 IND 类型 B 会议，以接收有关计划的 GLP 毒性研究和拟议的第一阶段协议的设计。在此应用的 UH3 阶段，我们将 1) 生产 GMP 工艺可比载体（GLP 载体），2) 在非人类灵长类动物和啮齿动物中进行计划的 GLP 药物/毒性研究，3) 生产 GMP 级载体，4) 准备和向 FDA 提交 IND，5) 在 SCA1 受试者中进行 I/II 期临床试验。