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RNAi Gene Silencing of alpha-Synuclein for Parkinson's Disease

RNAi 基因沉默 α-突触核蛋白治疗帕金森病

基本信息

批准号：
7211666
负责人：
Martha D Bohn
金额：
$ 16.08万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7211666
关键词：
Affect Alzheimer&apos s Disease Animal Model Basal Nucleus of Meynert Behavioral Brain Brain region Cell Death Cell Line Cells Cessation of life Chronic Clinic Clinical Clinical Trials Complex Cultured Cells Data Dementia Dependovirus Deterioration Development Disease Doctor of Philosophy Dopaminergic Cell Doxycycline Ectopic Expression Experimental Models Exposure to Gene Expression Gene Silencing Goals Histologic Histology Human In Vitro Individual Laboratories Lead Lentivirus Vector Lewy Bodies Lewy Body Disease Link Mitochondria Modeling Mus Nerve Degeneration Neurites Neurodegenerative Disorders Neurons Neurotoxins Parkinson Disease Parkinson&apos s Dementia Pathology Pesticides Pharmaceutical Preparations Point Mutation Process RNA Interference Range Rattus Research Personnel Role Rotenone SNCA gene Safety Structure Substantia nigra structure Syndrome Testing Toxic effect Triplet Multiple Birth Viral Vector adeno-associated viral vector alpha synuclein base behavior test cell growth design dopaminergic neuron dorsal motor nucleus gene therapy in vivo indexing inhibitor/antagonist locus ceruleus structure morphometry motor deficit multicatalytic endopeptidase complex mutant neurochemistry neuron loss neuroprotection nigrostriatal system nonhuman primate novel prevent programs promoter protein aggregate protein degradation small hairpin RNA synuclein therapeutic target vector viral RNA

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a debilitating neurodegenerative disease that affects over i million individuals in the US. Dementia with Lewy Bodies (DLB) is second in occurrence only to Alzheimer's disease. There are presently no treatments for PD or DLB that can halt or reverse the neurodegenerative processes. The RNA interference (RNAi) gene therapy approach in this project has the potential of halting or reversing these diseases. Recent studies suggest a role for a-synuclein (SNCA) in the development of PD and DLB, and other neurodegenerative diseases classified as a-synucleinopathies. Three point mutations in the SNCA gene, as well as triplet SNCA gene repeats, have been linked to familial forms of PD and DLB, revealing both mutant and wild type SNCA as therapeutic targets for these diseases. SNCA is a main components in neuronal inclusions called Lewy bodies, the neuropathological hallmarks of individuals afflicted with PD or DLB. In PD, Lewy bodies are found predominantly in the substantia nigra where the degenerating dopaminergic (DA) neurons reside. In DLB, Lewy bodies are found in many cortical and subcortical structures. Lewy neurites, neuronal processes containing insoluble SNCA protein, are found in both diseases. Insults that lead to death of DA neurons in animal models of PD, including exposure to the pesticide, rotenone, the neurotoxin, MPTP, and drugs that inhibit protein degradation increase SNCA expression and result in SNCA containing Lewy body-like inclusions in DA neurons. Moreover, experimentally increasing expression of human SNCA in a range of laboratory species leads to DA neuronal pathology and functional deterioration. We propose to explore the hypothesis that inhibiting expression of SNCA in DA neurons using a gene therapy approach will prevent DA neurodegeneration. Adeno-associated virus (AAV), the vector of choice for clinical trials will be used in rats in which human SNCA is ectopically expressed in DA neurons leading to DA cell death. The effects of silencing SNCA expression in this model, as well as in an SNCA-dependent cell culture model, will be assessed using morphometry, histology, neurochemistry and behavioral testing. Also, a vector with the silencing construct under control of an inducible promoter will be generated and tested as a possible safety strategy for a clinical gene therapy. The goal of this project is to generate proof-of-principle data supporting the development of clinical trials using a novel RNAi-based gene therapy for individuals afflicted with PD and DLB. ?

描述（由申请人提供）：帕金森病（PD）是一种使人衰弱的神经退行性疾病，在美国影响超过100万人。路易体痴呆（DLB）是仅次于阿尔茨海默病的第二大发病率。目前还没有治疗PD或DLB的方法可以阻止或逆转神经退行性过程。本项目中的RNA干扰（RNAi）基因治疗方法具有阻止或逆转这些疾病的潜力。最近的研究表明，a-突触核蛋白（SNCA）在PD和DLB以及其他被归类为a-突触核蛋白病的神经退行性疾病的发展中起作用。SNCA基因的三点突变以及SNCA基因的三重重复序列与家族性PD和DLB有关，这表明突变型和野生型SNCA都是这些疾病的治疗靶点。SNCA是称为路易体的神经元包涵体的主要成分，路易体是PD或DLB患者的神经病理学标志。在PD中，路易小体主要存在于退化的多巴胺能（DA）神经元所在的黑质中。在DLB中，路易小体见于许多皮层和皮层下结构。路易神经突是一种含有不溶性SNCA蛋白的神经元突起，在这两种疾病中都有发现。在PD动物模型中，导致DA神经元死亡的损伤，包括暴露于农药、鱼藤酮、神经毒素、MPTP和抑制蛋白质降解的药物，会增加SNCA的表达，导致DA神经元中SNCA含有路易体样包裹体。此外，在实验中，在一系列实验物种中增加人类SNCA的表达会导致DA神经元病理和功能恶化。我们提出探索利用基因治疗方法抑制DA神经元中SNCA的表达以防止DA神经退行性变的假设。腺相关病毒（AAV）是临床试验选择的载体，将用于人类SNCA在DA神经元中异位表达导致DA细胞死亡的大鼠。在该模型以及SNCA依赖性细胞培养模型中，沉默SNCA表达的效果将通过形态学、组织学、神经化学和行为测试进行评估。此外，在诱导启动子的控制下，将产生具有沉默结构的载体，并作为临床基因治疗的可能安全策略进行测试。该项目的目标是生成原理证明数据，支持使用基于rnai的新型基因治疗PD和DLB患者的临床试验的发展。？