AAV Gene Therapy for Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默氏症痴呆症的破坏今天花费1000亿美元，如果在未来十年不加以控制，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促发因素。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，但到目前为止，成功仍然难以捉摸。问题之一是，许多药剂的系统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，即使是抗Aa疫苗也不得不停止。本申请提出了一种相对较新的方法，通过利用基因治疗来提高Aa的清除率并减少Aa的产生来降低脑Aa。该方法将注射重组腺相关病毒载体（rAAV），已知安全地导致转导基因的稳定神经元表达，进入APP+P81转基因小鼠，可靠地存款淀粉样蛋白和发展学习和记忆缺陷。将转移蛋白酶以降解Aa或转移针对产生Aa的酶的抑制性RNA构建体的rAAV载体注射到海马和大脑皮层中。这些载体的有效性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，并在老年小鼠中评估其作为治疗剂的潜在效用。此外，我们将研究多种方法，以最大限度地提高整个神经系统中转移基因的分布。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。这些研究的结果将有望成为一种新的基因治疗方法，以消除阿尔茨海默氏痴呆症的灾难。

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.