Development of RNAi as Treatment for Neurodegeneration

描述（由申请人提供）：阿尔茨海默氏病，已经是一种严重的全球性疾病，困扰着大部分人口，随着婴儿潮一代泡沫接近退休年龄，它将成为一个更大的问题。这种疾病仍然无法治愈;然而，已知有效的治疗靶点。RNA干扰（RNAi）技术是一种潜在的治疗选择，需要进一步研究。靶向mRNA而不是蛋白质提供了易于设计高度特异性抑制剂的主要优势，并且快速推进的RNAi递送方法表明该方法可以开发成治疗方法。我们的假设是，RNAi将被证明是一种有效的和选择性的策略，以减缓，甚至逆转，遗传性和散发性AD的致病过程。本提案是在完成同一标题的R21奖之后提出的。该奖项的宣布是来自福格蒂研究所的RFA，用于与发展中国家脑部疾病有关的提案，该计划的主要目标是在国外建立研究能力。初步数据中描述了R21目标的成功完成情况。合作的努力提出了两个问题的原因和可能的治疗AD的神经病理学。一个问题是Cdk 5的抑制，一个越来越被接受的疾病靶点，是否可以改变动物模型中的神经病理学。cdk 5是一种使tau蛋白磷酸化的酶，并且在这样做的过程中被认为有助于将蛋白质转化为不溶性聚集体，称为神经元缠结。Cdk 5将通过在病毒载体中递送的RNAi靶向。第二个问题是通过RNAi递送的BACE 1抑制是否可以延缓或预防具有斑块和缠结的动物中神经病理学的发展。此处提议的研究旨在继续建设目前能够启动这些研究的国外研究中心的研究能力。除了Kosik实验室和国外工厂之间的既定合作外，两名顾问将为能力建设做出贡献。他们是Bev Davidson，他将建议建立一个病毒核心，Frank LaFerla将把三重转基因小鼠贡献给国外的动物园。

DESCRIPTION (provided by applicant): Alzheimer's disease, already a serious global disease afflicting large segments of the population, is about to burgeon into an even larger problem as the baby-boomer bubble approaches retirement age. The disease remains incurable; however validated therapeutic targets are known. RNA interference (RNAi) technology poses a potential therapeutic option which requires further investigation. Targeting the mRNA rather than the protein offers major advantages in the ease of designing a highly specific inhibitory agent and rapidly advancing approaches to RNAi delivery suggest that the method can be developed into a therapy. Our hypothesis is that RNAi will prove to be an effective and selective strategy to slow, and perhaps even reverse, the pathogenic processes in inherited and sporadic AD. This proposal follows the completion of an R21 award of the same title. The announcement for this award was an RFA from the Fogarty Institute for proposals related to Brain Disorders in the Developing World and a major goal of the program was to build research capacity at the foreign site. The successful completion of the R21 aims is described in the preliminary data. The collaborative effort poses two questions concerning the cause and possible treatment of neurofibrillary pathology in AD. One question is whether suppression of Cdk5, an increasingly accepted disease target, can modify neurofibrillary pathology in an animal model. Cdk5 is an enzyme that phosphorylates tau protein and in so doing is thought to contribute to the conversion of the protein into an insoluble aggregate known as the neurofibrillary tangle. Cdk5 will be targeted by RNAi delivered in a viral vector. The second question is whether BACE1 inhibition by RNAi delivery can retard or prevent the development of neurofibrillary pathology in an animal with both plaques and tangles. The studies proposed here are intended to continue building research capacity at the foreign site which is now in a position to launch these studies. In addition to the established collaboration between the Kosik laboratory and the foreign site, two consultants will contribute to capacity building. They are Bev Davidson who will advise on the establishment of a viral core and Frank LaFerla who will contribute the triple transgenic mice to the vivarium at the foreign site.