# Targeting the Unfolded Protein Response to Treat Retinitis Pigmentosa

> **NIH NIH R44** · OPTIKIRA, LLC · 2020 · $774,833

## Abstract

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.

## Key facts

- **NIH application ID:** 9936340
- **Project number:** 5R44EY026370-03
- **Recipient organization:** OPTIKIRA, LLC
- **Principal Investigator:** Richard McCulloch Keenan
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $774,833
- **Award type:** 5
- **Project period:** 2015-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936340

## Citation

> US National Institutes of Health, RePORTER application 9936340, Targeting the Unfolded Protein Response to Treat Retinitis Pigmentosa (5R44EY026370-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9936340. Licensed CC0.

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