AAV Gene Therapy for Alzheimer's Disease

描述(由申请人提供)：阿尔茨海默氏症造成的破坏今天耗资1000亿美元，如果未来十年不加以控制，将使美国的医疗保健在经济上陷入瘫痪。病理学和遗传学研究表明，AA肽的积聚是该病的主要诱发因素。使用传统小分子药物阻止这种积累的多种策略正在研究中，但到目前为止，成功仍然难以捉摸。一个问题是，许多药物的系统性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，即使是抗AA疫苗也不得不停止接种。这项应用提出了一种相对较新的方法，通过利用基因疗法来增强清除和减少AA的产生来降低大脑AA。该方法将向APP+P81转基因小鼠注射重组酸性相关病毒载体(RAAV)，这种载体可安全地导致转导基因的稳定神经元表达，从而可靠地沉积淀粉样蛋白并出现学习和记忆障碍。转移酶以降解AA的rAAV载体或转移针对产生AA的酶的抑制性RNA结构将被注射到海马区和大脑皮层。这些载体的有效性和安全性将在幼鼠身上进行测试，以评估它们作为预防治疗的能力，并在老年鼠身上评估它们作为治疗药物的潜在效用。此外，我们还将研究最大化转移基因在神经系统中分布的多种方法。具有治疗效果、最佳安全性和广泛分布的rAAV结构将被选为进一步开发用于治疗阿尔茨海默氏症的药物。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.