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: 7935490
• 负责人: Beverly L. Davidson
• 金额: $ 49.34万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935490
• 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; 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; Mental Depression; 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; 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）：本申请涉及广泛的挑战领域（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在细胞培养和啮齿动物模型中进行的研究RNAi作为神经系统疾病亨廷顿氏病（HD）的潜在治疗方法，并将这些发现应用于非人灵长类动物（NHP）。HD是一种致命的遗传疾病，由编码亨廷顿蛋白（HTT）的HTT突变引起，仅在美国就有大约3万人受到影响。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在脑部疾病的普遍应用，以及对HD的特殊重要性，有两个关键问题尚未得到解决。第一，长期应用治疗性RNAi治疗灵长类脑是否可行用于慢性神经退行性疾病，如HD？第二，灵长类动物的大脑是否能耐受正常和突变HTT等位基因的敲除？为了解决前一个问题，我们和其他人已经建立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，可以测试长期应用程序的问题，而不会出现重新交付的问题。在这个提议中，我们将测试使用重组腺相关病毒（AAV）载体的长期治疗性RNAi的可行性。为了解决第二个问题，我们在HD的啮齿动物模型中建立并测试了治疗性RNAi，并显示出疾病特异性表型的改善，包括生存率。有了这些工具，我们现在可以回答在一个更相关的模型中提出的问题，即正常的NHP（恒河猕猴；猕猴）。拟议的研究是两个实验室之间的合作：爱荷华大学的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。戴维森实验室有在啮齿动物中开发和测试RNAi疗法的经验，而Ojeda实验室在将病毒载体定向递送到NHP大脑方面具有专长。此外，ONPRC拥有方法、设备和人员，与Ojeda博士的团队一起，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大脑后诱导神经病理学或神经症状。虽然这些原理验证研究将为严格评估RNAi治疗HD提供一个平台，但从我们的工作中获得的信息可以应用于RNAi治疗其他慢性神经系统疾病，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’s病）、肌亢、脊髓小脑共济失调和Rett’s综合征。此外，我们的研究结果将为实验室研究RNAi治疗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）提供必要的工具。在这项工作中，我们将在非人类灵长类动物的临床相关模型中测试用于治疗致命神经遗传疾病亨廷顿氏病的基因疗法的安全性和有效性。实验旨在测试将治疗性基因沉默策略从啮齿动物模型的疗效研究转移到临床的相关问题，并解决有关这种治疗亨廷顿氏病的重要问题。这项工作是由爱荷华大学的实验室和俄勒冈健康科学大学的俄勒冈国家灵长类动物研究中心合作完成的。