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

亨廷顿病的 RNA 干扰疗法：在非人类灵长类动物中的研究

• 批准号: 8357819
• 负责人: Sergio R Ojeda
• 金额: $ 5.82万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357819
• 关键词: Address; Area; Behavioral; Brain; Cell Culture Techniques; Chronic; Collaborations; Disease; Equipment; Funding; Gene Silencing; Grant; Human Resources; Huntington Disease; Iowa; Macaca mulatta; Methodology; National Center for Research Resources; Neurologic; Oregon; Primates; Principal Investigator; RNA Interference; Research; Research Infrastructure; Resources; Rodent; Rodent Model; Safety; Source; Symptoms; Testing; Therapeutic; Translating; Translations; United States National Institutes of Health; Universities; Viral Vector; Work; clinically relevant; cost; experience; expression vector; nervous system disorder; neuropathology; nonhuman primate; putamen

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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 该应用解决了广泛的挑战领域 (15)：15-NS-102：基因沉默疗法的转化。 RFA 提出的挑战是将目前对 RNA 干扰 (RNAi) 疗法治疗慢性神经系统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临床上更相关的物种。目前的提案概述了一种系统的方法来转化我们和其他人已经开展的工作，以研究 RNAi 作为细胞培养和啮齿动物模型中神经系统疾病、亨廷顿病 (HD) 的潜在疗法，并将这些发现应用于非人类灵长类动物（NHP）。拟议的研究是爱荷华大学和俄勒冈国家灵长类动物研究中心（ONPRC）之间的合作。爱荷华大学拥有在啮齿类动物中开发和测试 RNAi 疗法的经验，而 ONPRC 则拥有将病毒载体立体定向递送至 NHP 大脑的专业知识。此外，ONPRC 拥有适当的方法、设备和人员，可以评估 HTT 抑制或一般 RNAi 的应用是否会在将 RNAi 表达载体递送到 NHP 大脑后诱发神经病理学或神经系统症状。迄今为止，我们已经证明可以将恒河猴壳核中的 HTT 表达降低 45%。 HTT 的这种抑制与任何行为异常的表现或壳核的神经病理学变化无关。