AAV Gene Therapy for Alzheimer's Disease

AAV 基因疗法治疗阿尔茨海默病

• 批准号: 6965442
• 负责人: David Morgan
• 金额: $ 36.8万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6965442
• 关键词: Alzheimer' s disease; RNA interference; adeno associated virus group; amyloid proteins; aspartic endopeptidases; behavior test; biotechnology; cerebral cortex; enzyme activity; enzyme induction /repression; enzyme linked immunosorbent assay; gene therapy; genetically modified animals; hippocampus; laboratory mouse; microarray technology; neprilysin; nervous system disorder therapy; nonhuman therapy evaluation; open field behavior; protein degradation; recombinant virus; ribozymes; transfection /expression vector

DESCRIPTION (provided by applicant): The devastation of Alzheimer's dementia costs $100 billion today and will economically cripple American health care if not controlled in the next decade. Pathology and genetic studies indicate the accumulation of the Aa peptide as a major precipitating factor in the disease. Multiple strategies using traditional small molecule drugs to arrest this accumulation are being investigated, but, thus far, success remains elusive. One; problem is that systemic application of many agents have unintended consequences outside the brain. Even the anti-Aa vaccines had to be halted due to unforeseen, serious adverse events. This application proposes a relatively new approach to lowering brain Aa by exploiting gene therapy to enhance the clearance and reduce the production of Aa. The approach will inject recombinant acieno-associated viral vectors (rAAV), known to safely result in stable neuronal expression of transduced genes, into APP+P81 transgenic mice, which reliably deposit a amyloid and develop learning and memory deficits. rAAV vectors transferring proteases to degrade Aa or transferring inhibitory RNA constructs against enzymes producing Aa will be injected into the hippocampus and cerebral cortex. Their efficacy and safety of these vectors will be tested in young mice, to evaluate their capacity as prophylactic treatments and in older mice to estimate their potential utility as therapeutics. Additionally, we will investigate multiple methods for maximizing the distribution of transferred genes throughout the nervous system. The rAAV construct with therapeutic efficacy, optimal safety and broad distribution will be selected for further development as a treatment for Alzheimer's. The outcome of these studies will, hopefully, be a novel gene therapeutic approach to dismantle the catastrophe of Alzheimer's dementia.

描述（由申请人提供）：阿尔茨海默氏痴呆症造成的破坏目前已造成 1000 亿美元的损失，如果在未来十年内不加以控制，将在经济上削弱美国的医疗保健。病理学和遗传学研究表明 Aa 肽的积累是该疾病的主要诱发因素。正在研究使用传统小分子药物来阻止这种积累的多种策略，但迄今为止，成功仍然难以捉摸。一;问题是，许多药物的全身应用会在大脑之外产生意想不到的后果。由于不可预见的严重不良事件，甚至连抗 Aa 疫苗也不得不停止。本申请提出了一种相对较新的方法，通过利用基因疗法来提高脑 Aa 的清除率并减少 Aa 的产生，从而降低脑 Aa 的水平。该方法将重组 acieno 相关病毒载体 (rAAV) 注射到 APP+P81 转基因小鼠中，这种载体已知可以安全地导致转导基因的神经元稳定表达，从而可靠地沉积淀粉样蛋白并产生学习和记忆缺陷。转移蛋白酶以降解 Aa 或转移针对产生 Aa 的酶的抑制性 RNA 构建体的 rAAV 载体将被注射到海马体和大脑皮层中。这些载体的功效和安全性将在年轻小鼠中进行测试，以评估其预防性治疗的能力，并在老年小鼠中进行测试，以估计其作为治疗药物的潜在效用。此外，我们将研究多种方法来最大化转移基因在整个神经系统中的分布。具有治疗功效、最佳安全性和广泛分布的rAAV构建体将被选择用于进一步开发作为阿尔茨海默病的治疗方法。这些研究的结果有望成为一种新的基因治疗方法，以消除阿尔茨海默氏症痴呆的灾难。