# Epigenetic modifiers as therapeutic agents to combat retinal degeneration

> **NIH NIH R21** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2020 · $191,625

## Abstract

Abstract
 Epigenetic remodeling of gene expression is a powerful therapeutic approach whose potential has yet
to be fully exploited. A number of degenerative diseases of the retina are good candidates for this approach
and this proposal focuses Retinitis Pigmentosa (RP), for which there are both excellent animal models and an
available patient population, but no treatments. In RP, mutant genes lead to the death of rod photoreceptors
and a secondary death of nearby cone photoreceptors that leads to blindness. Based on preliminary data we
have proposed the hypothesis that selective pharmacological manipulation of histone modifying enzymes will
alter the epigenetic landscape and lessen the impact of deleterious mutations, allowing extended survival of
rod photoreceptors in RP. To test this hypothesis we propose three specific aims.
 First, we will extend our preliminary findings to more fully define the optimum time course and dose of
LDS1 inhibitors (TCP and GSK2879552) that can block rod degeneration in the rd10 model of RP. We will
quantitate photoreceptor survival by immunocytochemistry, quantitative PCR, and OCT. We will also measure
visual function using ERG. We will use a second model of RP, the rd3 mouse, to test whether the effects can
be generalized to multiple forms of RP.
 Second, we will examine whether HDAC1 specific inhibitors can provide protection to rods in the same
models of RP. In a second series of experiments we will test whether use of LSD1 and HDAC1 inhibitors
together act synergistically to provide greater protection than either drug alone. Photoreceptor survival and
function will be monitored in the same way as in Aim 1.
 Third, we will analyze whether the epigenetic modifiers act to alter expression of the mutant genes and
gene in the same network, or have broader effects on processes such as apoptosis and inflammation. We will
use RNA-seq methods to give an unbiased measure of changes in gene expression induced by the LSD1 and
HDAC1 inhibitors. Key changes will be verified by qPCR. We will also measure changes in cytokines in the
retina and the vitreous to provide a quantitative estimate of levels of pro- and anti-inflammatory cytokines, and
changes in the activity of key signal pathways. Additionally, we will test whether changes in transcript or
protein levels are due to direct changes on the gene epigenetic status, by carrying out ChIP-seq for H3K4me2
(LSD1 substrate) and H3K9ac/12ac (HDAC1 substrate) as measures of promoter accessibility. These
experiments will provide insights into the mechanisms of protection and by analyzing the cellular networks
most altered will provide new targets for even more specific therapy.
 Overall, these experiments will provide important information about pathways that can prevent damage
in the retina and also offer a novel therapeutic approach that can combat RP and other retinal degenerations.

## Key facts

- **NIH application ID:** 9843157
- **Project number:** 5R21EY029992-02
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** COLIN J BARNSTABLE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $191,625
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843157

## Citation

> US National Institutes of Health, RePORTER application 9843157, Epigenetic modifiers as therapeutic agents to combat retinal degeneration (5R21EY029992-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9843157. Licensed CC0.

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