SBIR-STTR Award

?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. 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 IRE1? as the master unfolded protein response regulator that determines cell fate under ER stress, and have demonstrated that IRE1? 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: 1: To improve the profile of KIRAs for intraocular administration and efficacy; and, 2: To demonstrate optimized KIRAs boost efficacy in an ER stress model of rodent RP.

Public Health Relevance Statement:


Public Health Relevance:
Approximately 100,000 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.

NIH Spending Category:
Eye Disease and Disorders of Vision; Genetics; Neurodegenerative; Neurosciences; Rare Diseases

Project Terms:
Acute; Affect; American; analog; Aniline; Animal Model; Apoptosis; Attenuated; base; Benchmarking; Biological Assay; Biological Markers; Blindness; Cell Death; cell suicide; Cell Survival; Cells; Cessation of life; Chronic; Clinical; Cytoprotection; Defect; design; Development; Dimensions; Disease; Electroretinography; Endoplasmic Reticulum; endoplasmic reticulum stress; endoribonuclease; Endoribonucleases; Engineering; Genes; Genetic Models; glycosylation; Goals; Health; Histology; Human; improved; in vivo Model; Inflammation; Inherited; inhibitor/antagonist; Injection of therapeutic agent; kinase inhibitor; Lead; Link; Measures; Mediating; Messenger RNA; Molecular Genetics; mouse model; mRNA Transcript Degradation; Mus; Mutation; novel; novel strategies; novel therapeutic intervention; OmpR protein; Optical Coherence Tomography; Pathogenesis; Patients; Permeability; Pharmaceutical Preparations; Phase; Phosphotransferases; Photoreceptors; premature; Prevention; programs; protein folding; Proteins; public health relevance; response; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; Rhodopsin; Ribonucleases; Risk; RNA Splicing; Rodent; Rodent Model; Series; Severities; Signal Pathway; Signal Transduction; small molecule; Solubility; Sterility; Stress; Suicide; Testing; Therapeutic; transcription factor; Tunicamycin; Urea; Vertebrate Photoreceptors; Vision; Vitreous humor; Work

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 IRE1?, an ER transmembrane kinase/RNase, as the master UPR regulator that determines cell fate under ER stress and have demonstrated that IRE1? 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.

Public Health Relevance Statement:
NARRATIVE Approximately 100,000 Americans suffer from retinitis pigmentosa (RP), a disease that causes gradual retinal degeneration and eventual blindness. RP results from the premature death of photoreceptor cells in the back of the eye; cells that are responsible for transmitting signals from the visual field to the brain. To delay early photoreceptor death and blindness, we propose a novel strategy utilizing small molecules to target the unfolded protein response (UPR), a main cause of premature photoreceptor death. This work represents critical efforts to develop a disease-modifying intervention for RP and related blinding diseases.

Project Terms:
American; Animals; Apoptosis; Attenuated; Back; base; Blindness; Brain; Capital; Cell Death; Cell Differentiation process; Cell Survival; Cells; Cessation of life; Characteristics; Chronic; clinical candidate; Clinical Data; clinical development; Clinical Trials; Collaborations; commercialization; Coupled; Cytoprotection; Development; Disease; Drug Delivery Systems; drug development; Drug Industry; Endoplasmic Reticulum; endoplasmic reticulum stress; Endoribonucleases; Engineering; Exposure to; Eye; fighting; Formulation; Foundations; Fund Raising; Funding; Generations; Goals; Human; Inflammasome; Inherited; inhibitor/antagonist; Injectable; innovation; Intervention; kinase inhibitor; Lead; Medical; Messenger RNA; Modeling; Molecular Genetics; mRNA Transcript Degradation; Mus; Mutation; nano; Nature; novel; novel strategies; novel therapeutic intervention; novel therapeutics; OmpR protein; Ophthalmologist; Outcome; particle; Pathogenesis; Pathologist; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phosphotransferases; Photoreceptors; pre-clinical; Pre-Clinical Model; premature; preservation; product development; programs; protein folding; Proteins; Rattus; Resources; response; Retinal Degeneration; Retinal Pigments; retinal rods; Retinitis Pigmentosa; Rhodopsin; Ribonucleases; RNA Splicing; Rodent Model; Severities; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Small Business Technology Transfer Research; small molecule; small molecule inhibitor; small molecule therapeutics; Stress; Suicide; Suspensions; targeted treatment; Testing; Therapeutic; therapeutic target; transcription factor; treatment response; Vision; Visual Fields; Work; XBP1 gene