The development of gene therapeutic approaches to suppress cerebral inflammation in dementia

迫切需要开发新的有效治疗阿尔茨海默氏症的方法 疾病(AD)。基因治疗领域在过去的10年里取得了显著的进步，并开始 进入诊所接受疾病治疗。基因转移方法的优点是更有针对性 与更传统的方法相比，需要的干预措施要少得多。在AD字段中， 现在已经很清楚，炎症是导致AD病理的一个关键成分。一条主要路线是 炎症是通过激活炎症体来实现的，炎症体是细胞侮辱的感应器。因此，我们建议 发展抑制炎症体功能的基因转移方法。这将通过使用 脑部给药的炎症体复合体显性-阴性(DN)抑制剂(目标1)或通过 使用外周给药的炎症体复合体的脑靶向糖尿病肾病抑制剂(目标2)。腺体- 相关病毒(AAV)载体将用于促进糖尿病肾病抑制因子基因的表达，因为它们提供了 高效安全的病媒系统。我们将使用AD样淀粉样变性的大鼠转基因模型来测试这些 除神经化学和免疫组织学测量外，方法和评估学习/记忆 与AD关联。这项提案将探索AD的新治疗方法，目标是 相关动物模型中的炎症性疾病途径。

There is an urgent need for the development of new and effective therapeutic approaches to Alzheimer’s disease (AD). The field of gene therapy has progressed significantly in the last 10 years and is beginning to enter the clinic for disease treatment. Gene transfer approaches have the advantage of being more targeted to specific pathways and require far fewer interventions compared to more traditional approaches. In the AD field, it has become clear that inflammation is a key component contributing to AD pathology. One major route for inflammation is through activation of inflammasomes, sensors of cellular insults. Therefore, we propose the development of gene transfer approaches to inhibit inflammasome function. This will be done through the use of a brain administered dominant-negative (DN) inhibitor of the inflammasome complex (Aim 1) or through the use of a peripherally delivered brain-targeted DN inhibitor of the inflammasome complex (Aim 2). Adeno- associated viral (AAV) vectors will be used to facilitate DN inhibitor gene expression as they provide an efficient and safe vector system. We will use a rat transgenic model of AD-like amyloidosis to test these approaches and assess learning/memory in addition to neurochemical and immunohistological measure associated with AD. This proposal will explore novel therapeutic approaches to AD through targeting a key inflammatory disease pathway in a relevant animal model.