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

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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.