Development of RNAi as Treatment for Neurodegeneration

描述（由申请人提供）：阿尔茨海默病，已经是一种严重的全球性疾病，折磨着大部分人口，随着婴儿潮泡沫接近退休年龄，它将成为一个更大的问题。这种疾病仍然无法治愈；然而，有效的治疗靶点是已知的。RNA干扰（RNAi）技术提供了一种潜在的治疗选择，需要进一步的研究。针对mRNA而不是蛋白质提供了设计高度特异性抑制剂的主要优势，并且快速发展的RNAi递送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和选择性的策略，可以减缓甚至逆转遗传性和散发性阿尔茨海默病的致病过程。该提案是在完成R21奖项之后提出的。该奖项是福格蒂研究所（Fogarty Institute）为发展中国家大脑疾病相关提案颁发的RFA，该计划的一个主要目标是在国外建立研究能力。初步数据描述了R21目标的成功完成。合作的努力提出了两个问题，关于阿尔茨海默病的神经原纤维病理的原因和可能的治疗。一个问题是，在动物模型中，抑制Cdk5（一个越来越被接受的疾病靶点）是否可以改变神经原纤维病理。Cdk5是一种磷酸化tau蛋白的酶，这样做被认为有助于将蛋白质转化为一种称为神经原纤维缠结的不溶性聚集体。Cdk5将被通过病毒载体传递的RNAi靶向。第二个问题是，在同时存在斑块和缠结的动物中，通过RNAi递送抑制BACE1是否可以延缓或防止神经原纤维病理的发展。这里提出的研究是为了继续在国外场址建设研究能力，因为国外场址现在有能力开展这些研究。除了Kosik实验室和国外基地之间已建立的合作之外，两名顾问将为能力建设作出贡献。他们是贝弗·戴维森，他将建议建立一个病毒核心，弗兰克·拉弗拉，他将把三倍转基因小鼠贡献给国外基地的动物实验室。

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.