Anti-Inflammatory gene therapy for age-related macular dengenration

Age-related macular degeneration (AMD) is the leading cause of blindness in elderly Americans and affects 30 million worldwide. Despite numerous clinical trials aimed at a diverse assortment of therapeutic targets, no approved therapy exists to prevent, delay or reverse blindness for those suffering from the more common atrophic or ‘dry’ form of AMD. The current dogma of molecular targeting in atrophic AMD relates to identifying and inhibiting a single causal factor responsible for AMD, which betrays the growing understanding of AMD as a multifaceted disease arising from a confluence of factors. A surprising number of AMD-related stimuli share a common pathway known as inflammasome signaling to promote retinal degeneration, suggesting that therapeutic inhibition of inflammasome signaling will prevent retinal degeneration resulting from multiple co-incident AMD drivers. In this proposal, we will advance novel, clinically relevant therapeutic inhibitors of MYD88, a requisite adaptor of the inflammasome effectors interleukins-1â and -18 via the following Specific Aims: 1) Construct optimization and production. Here we will optimize an existing effective peptide inhibitor to enhance its potency, specificity and safety. 2) AAV-MYD88i construct characterization and validation. Here we will evaluate the therapeutic efficacy of a novel AAV-based MYD88 inhibitor. Successful completion of these Aims will advance a novel therapeutic for an untreatable blinding disease affecting millions, as well as transform the prevailing paradigm from that of “piecemeal” targeting towards attacking a common element of disease pathogenesis.