ABSTRACT Approximately 100,000 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 for treatment of patients. We have assembled a comprehensive team of accomplished geneticists, ophthalmologists, cell biologists, pathologists, and pharmaceutical industry experts in medicinal chemistry and ocular drug delivery at OptiKira to achieve a single goal of developing a therapy to preserve vision in patients with RP. There is compelling evidence implicating endoplasmic reticulum (ER) stress in the pathogenesis of many forms of RP, especially those caused by autosomal dominant protein-folding mutations in Rhodopsin (ADRP). Through a longstanding collaboration, OptiKira and its founders have 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 that accelerates photoreceptor cell loss and blindness. We have identified IRE1α, an ER transmembrane kinase/RNase, as the master UPR regulator that determines cell fate under ER stress and have demonstrated that IRE1α inhibitors we call OPK-KIRAs (OptiKira-Kinase Inhibiting RNase Attenuators) provide functional cytoprotection to ER stress-challenged photoreceptors. This Phase II SBIR is organized into two coordinated Specific Aims that employ a succinct development pathway to advance our most promising compound into the IND-enabling phase. This work represents a focused drug development approach to develop a new class of agents with disease-modifying potential for RP. During Phase I STTR, we have synthesized, and identified highly potent and selective OPK- KIRAs. In Aim 1, we will use the selected compound to develop a delivery strategy to achieve sustained intraocular exposure to OPK-KIRAs. In Aim 2, we propose to demonstrate chronic efficacy of ocular KIRAs in rodent models of ADRP with the goal of selecting a clinical candidate for IND-enabling studies. In summary, we propose a novel strategy to protect photoreceptors from triggering their UPR suicide program, which if successful may lead to new proprietary drugs to treat RP and related blinding diseases.