IRE1 alpha inhibitors for Retinal Degenerative Diseases

DESCRIPTION provided by applicant Approximately Americans suffer from vision loss due to Retinitis Pigmentosa RP Despite significant progress in elucidating the molecular genetics of RP over the past three decades no disease modifying therapies have been approved There is compelling evidence implicating endoplasmic reticulum ER stress in the pathogenesis of various forms of RP especially those caused by autosomal dominant protein folding mutations in Rhodopsin ADRP Our team has uncovered key mechanisms whereby the unfolded protein response UPR an intracellular signaling pathway activated by ER stress promotes either cell survival or cell death depending on the severity of the stress Dominantly inherited Rhodopsin mutations generate high chronic ER stress to promote photoreceptor cell loss and blindness We have identified IRE as the master unfolded protein response regulator that determines cell fate under ER stress and have demonstrated that IRE inhibitors we call KIRAs Kinase Inhibitor RNase Attenuators provide functional cytoprotection to ER stress challenged photoreceptors We propose to optimize KIRAs for intravitreal administration and determine photoreceptor cytoprotection efficacy in an acute in vivo model of ER stress driven retinal degeneration This work represents early steps towards developing a new class of agents for RP with disease modifying potential The specific Aims of this proposal are To improve the profile of KIRAs for intraocular administration and efficacy and To demonstrate optimized KIRAs boost efficacy in an ER stress model of rodent RP PUBLIC HEALTH RELEVANCE Approximately Americans suffer from retinitis pigmentosa RP an untreatable blinding disease that results from the premature death of photoreceptors e g rods and cones We have evidence in animal models of RP that photoreceptors inappropriately activate an internal suicide program and that stopping this cell suicide program preserves vision In this proposal we explore a novel strategy to protect photoreceptors from triggering their internal suicide program which if successful may lead to new drugs to treat RP and related blinding diseases