Development of RNAi as Treatment for Neurodegeneration

描述(申请人提供)：直到最近，安蒂奥基亚还是一个基因隔离的国家，随着其人口的现代快速扩张，这个哥伦比亚国家由于最初的创始人效应而承受着严重的基因负担。特别是，迟发性神经退行性疾病在几个村庄几乎以流行的比例出现。大家族的特征是阿尔茨海默病、亨廷顿病、帕金森病和CADASIL的遗传形式。通过各种合作和哥伦比亚科学家多年来面对有限资源的坚持不懈，现在所有受影响的家庭都知道了负有责任的基因突变。我们对全球神经变性问题的许多关键见解都源于那些相对罕见的具有这些疾病遗传形式的家庭。尽管显性基因突变在所有阿尔茨海默病病例中所占比例不到1%，但治疗靶点的发现和验证来自于这些家族中发现的基因，如早老素和淀粉样前体蛋白(APP)基因，这些基因在家族性阿尔茨海默病中被发现。正如我们在1997年报告的(JAMA 277：793-799)，安蒂奥基亚市的家族性阿尔茨海默病家族是世界上这种疾病的最大聚集者，家谱现在由5000多个个体组成。这一血统提供了大量的信息，也是国际和平组织和外国科学家之间持续和富有成效的合作的来源。这种合作中缺少的是在国外站点执行以实验室为基础的计划的坚实基础。在这种类型的国际研究中，合作的科学家往往是为了收获独特的遗传资源，而没有为当地一群有才华的科学家创造机会，将他们自己的临床和流行病学工作转化为实验室领域。实验室研究是充分了解这一遗传资源并为快速增长的问题开发治疗方法的必要扩展。我们已经设计了一个项目，将在当地建立研究能力，并可能影响哥伦比亚和世界各地神经退行性疾病的治疗。Kosik实验室的工作已经证明了使用RNA干扰抑制哺乳动物神经元中基因表达的可行性(PNAS99：11926-9,2002年)。我们计划的科学目标是开发RNAi方法来“下调”BACE的表达，BACE是一种参与APP裂解成A-β的酶。我们还将使用类似的方法来敲除亨廷顿病，这种突变会导致亨廷顿病。这些实验为哥伦比亚科学家直接参与下一阶段的研究开辟了道路，而不仅仅是描述遗传学，哥伦比亚小组在这方面做出了如此巨大的贡献。

DESCRIPTION (provided by applicant): Antioquia was until recently a genetic isolate and with the modern rapid expansion of its population this Colombian state has sustained a serious genetic burden due to the original founder effects. In particular, late onset neurodegenerative diseases have emerged at nearly epidemic proportions in several villages. Large kindreds have been characterized with genetic forms of Alzheimer's disease, Huntington's disease, Parkinson's disease, and CADASIL. Through a variety of collaborations and the persistence of Colombian scientists over many years in the face of limited resources, the responsible gene mutations are now known in all of the affected families. Many of our key insights to the global problem of neurodegeneration have stemmed from those relatively rare families with genetic forms of these diseases. Although dominant gene mutations account for less than 1% of all cases of Alzheimer's, the discovery and validation of therapeutic targets has come from genes identified in these families such as presenilin and the amyloid precursor protein (APP) gene, which were identified in familial Alzheimer's disease. As we reported in 1997 (JAMA 277:793-799), the familial Alzheimer kindred in Antioquia are the largest aggregation of this disease in the world with family trees now consisting of over 5000 individuals. This pedigree has been enormously informative and the source of an ongoing and productive collaboration between the PI and scientists at the foreign site. What has been missing from this collaboration is a sound basis at the foreign site for the execution of a laboratory-based program. In international research of this sort, too often collaborating scientists come to harvest a unique genetic resource without creating an opportunity for a talented group of local scientists to translate their own clinical and epidemiologic work into the laboratory sphere. Laboratory studies represent an essential extension to fully understand this genetic resource and to develop approaches toward treatment for a rapidly growing problem. We have designed a program that will build research capacity at the local site and possibly impact the treatment of neurodegenerative disease both in Colombia and worldwide. Work in the Kosik lab has demonstrated the feasibility of using RNAi to suppress gene expression in mammalian neurons (PNAS 99:11926-9, 2002). The scientific goals of our program are to develop RNAi approaches to 'knock-down' expression of BACE, an enzyme involved in the cleavage of APP to A-beta. We will also use a similar approach to knock-down Huntington, mutations in which lead to Huntington's disease. These experiments open the way for the Colombian scientists to participate directly in the next phase of the research beyond descriptive genetics in which the Colombian group has made such a strong contribution.