RNA INTERFERENCE THERAPY FOR HUNTINGTON'S DISEASE: STUDIES IN NON-HUMAN PRIMATES

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 本申请涉及广泛的挑战领域(15)：15-NS-102：基因沉默疗法的翻译。RFA中提出的挑战是将目前对RNA干扰(RNAi)疗法用于治疗慢性神经疾病的可行性和安全性的理解从啮齿动物疾病模型扩展到更具临床相关性的物种。目前的提案概述了一种系统的方法来翻译我们和其他人致力于研究RNAi作为一种潜在的治疗神经疾病、细胞培养中的亨廷顿病(HD)和啮齿动物模型的工作，并将这些发现应用于非人类灵长类动物(NHP)。这项拟议的研究是爱荷华州大学和俄勒冈州国家灵长类研究中心(ONPRC)的合作项目。爱荷华大学有在啮齿动物身上开发和测试RNAi疗法的经验，而ONPRC在通过立体定位将病毒载体输送到NHP大脑方面拥有专业知识。此外，ONPRC拥有方法学、设备和人员，可以评估在将RNAi表达载体输送到NHP大脑后，应用HTT抑制或RNAi是否会导致神经病理或神经症状。到目前为止，我们已经证明了将htt在恒河猴壳核中的表达减少45%的效果。这种对HTT的抑制与壳核的任何行为异常或神经病理变化的表现无关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This application addresses broad Challenge Area (15): 15-NS-102: Translation of Gene Silencing Therapeutics. The proposed challenge set forth in the RFA is to extend the current understanding of the feasibility and safety of RNA interference (RNAi) therapeutics for the treatment of chronic neurological disorders from rodent models of disease to a more clinically relevant species. The current proposal outlines a systematic approach to translate work we, and others, have undertaken to investigate RNAi as a potential therapy for the neurological disorder, Huntington's disease (HD) in cell culture and rodent models and apply these findings to the non-human primate (NHP). The proposed studies are a collaboration between the University of Iowa and the Oregon National Primate Research Center (ONPRC). University of Iowa has experience developing and testing RNAi therapeutics in rodents, while the ONPRC has expertise in stereotaxic delivery of viral vectors to the NHP brain. Also, the ONPRC has methodologies, equipment and personnel in place that can evaluate if application of HTT suppression, or RNAi in general, induces neuropathology or neurological symptoms after delivery of RNAi expression vectors to NHP brain. To date, we have shown efficacy of reducing HTT expression in the rhesus macaque putamen by 45%. This suppression of HTT is not associated with the manifestation of any behavioral abnormalities nor neuropathological changes in the putamen.