RNAi Therapy for Spinocerebellar Ataxia Type 1

描述（由申请人提供）：脊髓小脑性共济失调1型（SCA 1）是9种多聚谷氨酰胺扩增疾病之一，其特征为小脑性共济失调和小脑和脑干中的神经元变性。目前，对这种疾病没有有效的治疗策略。以前，我们发现RNA干扰（RNAi）介导的共济失调蛋白-1 mRNA沉默在SCA 1小鼠模型中提供了治疗益处。腺相关病毒（AAV）递送靶向共济失调蛋白-1的microRNA（miRNA）至成熟的SCA 1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进我们的领先载体，这些里程碑将引导我们进入人类受试者的1期临床试验。在本申请的UH 2阶段，我们将1）在非人灵长类动物中对拟定载体进行可比性检测，以确认我们拟定的给药方案，2）与FDA CBER举行IND前B型会议，以接收有关计划GLP毒理学研究设计和拟定I期方案的输入。在本申请的UH 3阶段，我们将1）生产GMP工艺可比载体（GLP载体），2）在非人灵长类动物和啮齿类动物中进行计划的GLP药理学/毒理学研究，3）生产GMP级载体，4）制备IND并向FDA备案，5）在SCA 1受试者中进行I/II期临床试验。

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.