# Targeting Nr2e3 to prevent photoreceptor degeneration

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $504,014

## Abstract

Project Summary
Retinitis pigmentosa (RP) is the most common form of retinal dystrophy and can be caused by mutations in any
one of dozens of rod-enriched genes. The genetic heterogeneity of RP represents a major challenge for the
development of effective therapies. For this reason, gene-independent treatments for RP have become a long-
sought goal in vision research. In this proposal, we will test the hypothesis that knockout of the rod-specific
transcription factor Nr2e3 prevents photoreceptor degeneration in multiple mouse disease models. In Specific
Aim 1, we will characterize the neuroprotective effects of developmental Nr2e3 knockout in multiple models of
photoreceptor degeneration, including a light-damage model and four mechanistically diverse models of RP
(Pde6brd10/rd10, RhoP23H/+, Rho-/- and Cngb1-/-). We will use a combination of molecular, cellular, physiological, and
behavioral assays to evaluate the efficacy and versatility of this therapeutic approach. In Specific Aim 2, we will
evaluate the therapeutic potential of acute, adeno-associated virus (AAV)-delivered, CRISPR-Cas9-mediated
Nr2e3 knockout in the same four mouse RP models used in Aim 1. For each model, we will evaluate the ability
of acute Nr2e3 knockout to protect photoreceptors at multiple stages of degeneration. We will also compare the
effects of acute Nr2e3 knockout to those of Nr2e3 overexpression, which has also been suggested to prevent
degeneration. Together, these studies will test the effectiveness of Nr2e3-based reprogramming as a gene-
independent therapy for RP. Finally, in Specific Aim 3, we will determine the effects of acute Nr2e3 knockout in
wild-type mouse rods and identify neuroprotective factors downstream of Nr2e3. We will first compare the effects
of acute Nr2e3 knockout to those of developmental Nr2e3 knockout. We will then perform RNA-seq on Nr2e3-
knockout rods to generate a list of Nr2e3-downstream candidate effector genes. We will knockout or overexpress
selected candidate genes, singly and in combination, in four mouse models of RP to identity those that confer a
neuroprotective effect. If successful, these studies will establish Nr2e3 knockout as a novel gene-independent
therapy for RP, paving the way for future studies in large-animal models of photoreceptor degeneration and for
clinical studies in human patients.

## Key facts

- **NIH application ID:** 10783760
- **Project number:** 5R01EY033810-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** JOSEPH CORBO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $504,014
- **Award type:** 5
- **Project period:** 2023-03-01 → 2028-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10783760

## Citation

> US National Institutes of Health, RePORTER application 10783760, Targeting Nr2e3 to prevent photoreceptor degeneration (5R01EY033810-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10783760. Licensed CC0.

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