# Reprogramming the metabolome to overcome the genetic heterogeneity in retinitis pigmentosa

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $392,850

## Abstract

Project Summary
Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy, caused by >71 mutations that
primarily cause rod photoreceptor death. Cone death always follows rod
death and starts after the end of major
rod death phase regardless of the underlying rod specific gene mutations. Accumulation evidence have shown
that cone death in RP is due to glucose starvation. There is a knowledge gap in understanding cellular
metabolism in cone and “metabolic coupling” between cone and RPE in RP. Our long-term goal is to prevent
blindness in RP due to cone death. Our overall objective is to define how cones and RPE are metabolically
coupled and to test potential therapies for RP that are designed to restore this relationship. Our central
hypothesis is that reprogramming cone and RPE metabolism can promote cone survival in RP
independently of the underlying rod-specific gene mutations. To test this hypothesis, we propose three
specific aims. In Aim 1, we will use a cone-specific conditional allele to enhance glycolysis or OXPHOS in
cone cells and then determine the effects on cone survival and function in RP mouse models. In Aim 2, we will
use an RPE-specific conditional allele to enhance or suppress OXPHOS in RPE and determine the effects on
photoreceptor function in RP mouse models. The results from Aim 1 & 2 will elucidate the role of glycolysis
and OXPOHS in Cone and RPE cells in mouse model of RP. In Aim 3, we will use virus gene therapy to test
therapeutic value of reprogramming cone and RPE metabolisms in 2 preclinical models of RP. Impact: it will
address this knowledge gap in cone metabolism and the role of OXPHOS in RPE biology in degenerated
retina, which will greatly advance our understanding of the metabolic coupling between cones and the RPE
and may provide opportunities for preclinical gene-therapy interventions to prevent cone death or delay
photoreceptor degeneration through reprogramming of cellular metabolism. This proposal is innovative
because it: 1) will use innovative inducible cell-specific Cre drivers to address previously unanswered
questions that require precise control of timing of gene manipulation in cones and RPE; 2) will use innovative
conditional overexpress knock-in mouse ; 3)will be the first to test innovative hypothesis that reprogramming
cone and RPE metabolism can promote cone survival in RP independently of the underlying rod specific gene
mutations; 4) will use unique knock-in mouse model of RP; and 5) will test preclinical animal trial using
AAV::Cone specific CRISPR/Cas9 to target a gene to reprogram cellular metabolism.

## Key facts

- **NIH application ID:** 10459428
- **Project number:** 5R01EY031354-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Nan-Kai Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $392,850
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459428

## Citation

> US National Institutes of Health, RePORTER application 10459428, Reprogramming the metabolome to overcome the genetic heterogeneity in retinitis pigmentosa (5R01EY031354-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10459428. Licensed CC0.

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