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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 该应用程序解决了广泛的挑战领域（15）：15-NS-102：基因沉默疗法的翻译。 RFA中提出的挑战是将当前对RNA干扰（RNAI）疗法的可行性和安全性的理解用于治疗慢性神经系统疾病，从疾病的啮齿动物模型到更临床相关的物种。当前的提案概述了一种系统的方法来翻译我们和其他人的工作，将RNAi作为神经系统疾病，亨廷顿氏病（HD）的潜在疗法进行研究，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州国家灵长类动物研究中心（ONPRC）之间的合作。爱荷华大学具有在啮齿动物中开发和测试RNAi治疗剂的经验，而ONPRC在立体定位向NHP大脑的立体定位传递方面具有专业知识。此外，ONPRC具有可以评估HTT抑制或RNAi通常会在将RNAi表达载体传递到NHP脑后的神经病理学或神经系统症状的方法，设备和人员。迄今为止，我们已经显示出将猕猴钉在45％的HTT表达中的功效。这种对HTT的抑制与壳虫中任何行为异常或神经病理学变化的表现无关。