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）：阿尔茨海默氏症痴呆症的破坏今天成本为1000亿美元，如果在未来十年不受控制的情况下，经济上会削弱美国的医疗保健。病理和遗传研究表明AA肽作为疾病中的主要降水量因子的积累。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，但到目前为止，成功仍然难以捉摸。一;问题是，许多代理的全身应用在大脑之外会产生意想不到的后果。由于不可预见的严重不良事件，也必须停止抗AA疫苗。该应用提出了一种相对较新的方法来通过利用基因疗法来降低大脑AA，以增强清除率并减少AA的产生。该方法将在APP+p81转基因小鼠中注入重组囊型相关病毒载体（RAAV），该病毒载体（RAAV）可安全地导致转导基因的稳定神经元表达，这些小鼠可靠地沉积淀粉样蛋白并发展学习和记忆缺陷。转移蛋白酶以降解AA或针对产生AA酶的抑制性RNA构建体的RAAV载体将注入海马和大脑皮层。这些载体的功效和安全性将在年轻小鼠中进行测试，以评估其作为预防性治疗的能力和老鼠的能力，以估计其作为治疗剂的潜在效用。此外，我们将研究多种方法，以最大程度地提高整个神经系统中转移基因的分布。将选择具有治疗功效，最佳安全性和广泛分布的RAAV构造作为对阿尔茨海默氏症的治疗的进一步开发。希望这些研究的结果将是消除阿尔茨海默氏症灾难的一种新型基因治疗方法。