Development of RNAi as Treatment for Neurodegeneration

描述(申请人提供)：阿尔茨海默氏症已经是一种严重的全球性疾病，困扰着大部分人口，随着婴儿潮一代的泡沫接近退休年龄，阿尔茨海默氏症即将发展成为一个更大的问题。这种疾病仍然无法治愈；然而，已知有效的治疗目标。RNA干扰(RNAi)技术提供了一种潜在的治疗选择，需要进一步研究。靶向mRNA而不是蛋白质在设计高度特异的抑制剂方面提供了主要优势，快速发展的RNAi传递方法表明该方法可以发展为一种治疗方法。我们的假设是，RNAi将被证明是一种有效的选择性策略，可以减缓甚至逆转遗传性和散发性AD的致病过程。这项提议是在同一头衔的R21奖项完成后提出的。这一奖项的宣布是来自Fogarty研究所的与发展中国家大脑疾病相关的建议的RFA，该计划的一个主要目标是在外国网站建设研究能力。初步数据描述了成功完成R21 AIMS的情况。这项合作工作提出了两个问题，涉及阿尔茨海默病的神经纤维病理的原因和可能的治疗。一个问题是，抑制CDK5，一个日益被接受的疾病靶点，是否可以改变动物模型中的神经原纤维病理。CDK5是一种将tau蛋白磷酸化的酶，在这样做的过程中，被认为有助于将该蛋白转化为一种被称为神经原纤维缠结的不溶性聚集体。CDK5将被病毒载体中的RNAi靶向。第二个问题是，在既有斑块又有缠结的动物中，通过RNAi传递抑制BACE1是否可以延缓或阻止神经原纤维病变的发展。这里提出的研究意在继续建设外国网站的研究能力，该网站现在能够启动这些研究。除了Kosik实验室与外国站点之间已建立的合作之外，两名顾问还将为能力建设作出贡献。他们是Bev Davidson，他将为建立病毒核心提供建议，Frank LaFerla，他将把三重转基因小鼠捐赠给外国网站的隔膜。

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.