RNA interference therapy for Huntington's disease: studies in non-human primates

RNA 干扰疗法治疗亨廷顿病：在非人类灵长类动物中的研究

• 批准号: 7816168
• 负责人: Beverly L. Davidson
• 金额: $ 43.96万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7816168
• 关键词: Address; Adult; Affect; Alleles; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Anxiety; Area; Behavioral; Brain; Brain Diseases; Brain scan; Carcinoma; Cell Culture Techniques; Chronic; Classification; Clinic; Clinical; Collaborations; Corpus striatum structure; Data; Dependovirus; Disease; Dystonia; Emotional Disturbance; Encephalitis; Equipment; Euthanasia; Excision; Gene Expression; Gene Silencing; Genes; Genetic Polymorphism; Health Sciences; Hereditary Disease; Home environment; Human; Human Resources; Huntington Disease; Hyperactive behavior; Impaired cognition; In Vitro; Inborn Genetic Diseases; Injection of therapeutic agent; Iowa; Laboratories; Left; Link; Macaca; Macaca mulatta; Magnetic Resonance Imaging; Measures; Mediating; Messenger RNA; Methodology; MicroRNAs; Modeling; Molecular; Monitor; Motor; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Oregon; Parkinson Disease; Patients; Peripheral; Phenotype; Primates; RNA Interference; Rattus; Recombinant adeno-associated virus (rAAV); Reporting; Research; Rett Syndrome; Rodent; Rodent Model; Safety; Small Interfering RNA; Spinocerebellar Ataxias; Symptoms; Testing; Therapeutic; Tissues; Transcript; Translating; Translations; United States; Universities; Viral Vector; Work; adeno-associated viral vector; base; clinically relevant; depression; design; experience; expression vector; gait examination; gene therapy; human Huntingtin protein; improved; in vivo; knock-down; mouse model; mutant; nervous system disorder; neurogenetics; neuropathology; nonhuman primate; painful neuropathy; research study; safety testing; therapeutic gene; therapy design; tool

DESCRIPTION (provided by applicant): 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). HD is a fatal, genetic disorder caused by mutations in HTT, which encodes huntingtin (HTT), and affects approximately 30,000 people in the United States alone. HD is characterized by hyperkinetic movements, loss of cognitive abilities and severe emotional disturbances. RNAi has emerged as a candidate therapy for HD because it can reduce disease gene expression. However two critical questions important to the general application of RNAi to brain disorders, and of specific importance to HD, have yet to be addressed. One, is long-term application of therapeutic RNAi to primate brain feasible for chronic neurodegenerative diseases like HD? Second, is the primate brain tolerant of knock down of both normal and mutant HTT alleles? To address the former question we, and others, have built the tools necessary for sustained expression of candidate therapeutic RNAi in brain using viral vectors. In this manner, questions of chronic application can be tested without re-delivery issues. In this proposal we will test the feasibility of long-term therapeutic RNAi using recombinant adeno-associated virus (AAV) vectors. To address the second question, we have built and tested therapeutic RNAi in rodent models of HD, and show improvements in disease-specific phenotypes, including survival. With these tools we can now answer the questions posed in a more relevant model, the normal NHP (rhesus macaque; Macaca mullata). The proposed studies are a collaboration between two laboratories: the Davidson Laboratory at the University of Iowa and the Ojeda Laboratory at the Oregon National Primate Research Center (ONPRC). The Davidson Laboratory has experience developing and testing RNAi therapeutics in rodents, while the Ojeda Laboratory has expertise in stereotaxic delivery of viral vectors to the NHP brain. Also, the ONPRC has methodologies, equipment and personnel in place that, along with Dr. Ojeda's group, 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. While these proof-of-principle studies will provide a platform to rigorously evaluate RNAi therapeutics for HD, information derived from our work can be applied to RNAi therapies for other chronic, neurological disorders including, but not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (Lou Gherig's disease), dystonia, spinocerebellar ataxias and Rett's Syndrome. Moreover, the results from our studies will provide the necessary tools for laboratories investigating RNAi therapy for other brain disorders in the NHP, such as neuropathic pain, encephalitis, various carcinomas, anxiety and depression. In this work we will test the safety and efficiency of gene therapies designed to treat the fatal neurogenetic disorder, Huntington's disease, in a clinical relevant model, the nonhuman primate. Experiments are designed to test questions relevant to moving therapeutic gene silencing strategies from efficacy studies in rodent models to the clinic, and to address important issues regarding this therapy for Huntington's disease. This work is a collaborative effort between laboratories at the University of Iowa and the Oregon National Primate Research Center at the Oregon Health Sciences University.

描述（由申请人提供）：本申请解决了广泛的挑战领域（15）：15-NS-102：基因沉默疗法的翻译。 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）。 HD 是一种致命的遗传性疾病，由编码亨廷顿蛋白 (HTT) 的 HTT 突变引起，仅在美国就影响约 30,000 人。 HD 的特点是运动过度、认知能力丧失和严重的情绪障碍。 RNAi 已成为 HD 的候选疗法，因为它可以减少疾病基因的表达。然而，对于 RNAi 在脑部疾病中的普遍应用以及对 HD 特别重要的两个关键问题尚未得到解决。第一，对灵长类动物大脑长期应用治疗性 RNAi 治疗 HD 等慢性神经退行性疾病是否可行？其次，灵长类动物大脑是否能够耐受正常和突变 HTT 等位基因的敲除？为了解决前一个问题，我们和其他人已经构建了使用病毒载体在大脑中持续表达候选治疗性 RNAi 所需的工具。通过这种方式，可以测试长期应用的问题，而不会出现重新交付问题。在本提案中，我们将测试使用重组腺相关病毒 (AAV) 载体进行长期治疗性 RNAi 的可行性。为了解决第二个问题，我们在 HD 啮齿动物模型中构建并测试了治疗性 RNAi，并显示出疾病特异性表型（包括生存率）的改善。有了这些工具，我们现在可以回答一个更相关的模型，即正常 NHP（恒河猴；Macaca mullata）中提出的问题。拟议的研究是两个实验室之间的合作：爱荷华大学戴维森实验室和俄勒冈国家灵长类动物研究中心（ONPRC）的奥赫达实验室。戴维森实验室拥有在啮齿类动物中开发和测试 RNAi 疗法的经验，而奥赫达实验室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，可以与 Ojeda 博士的团队一起评估 HTT 抑制或一般 RNAi 的应用是否会在将 RNAi 表达载体传递到 NHP 大脑后诱发神经病理学或神经系统症状。虽然这些原理验证研究将为严格评估 HD 的 RNAi 疗法提供一个平台，但从我们的工作中获得的信息可以应用于其他慢性神经系统疾病的 RNAi 疗法，包括但不限于阿尔茨海默病、帕金森病、肌萎缩侧索硬化症（Lou Gherig 病）、肌张力障碍、脊髓小脑共济失调和雷特氏病 综合症。此外，我们的研究结果将为研究 NHP 中其他脑部疾病（如神经性疼痛、脑炎、各种癌症、焦虑和抑郁）的 RNAi 疗法的实验室提供必要的工具。在这项工作中，我们将在临床相关模型（非人类灵长类动物）中测试旨在治疗致命的神经遗传性疾病亨廷顿病的基因疗法的安全性和有效性。实验旨在测试与将治疗性基因沉默策略从啮齿动物模型的功效研究转移到临床相关的问题，并解决与这种亨廷顿病疗法有关的重要问题。这项工作是爱荷华大学实验室和俄勒冈健康科学大学俄勒冈国家灵长类动物研究中心之间的合作成果。