# Precision Medicine for Inherited Retinal Degenerations

> **NIH NIH R01** · MASSACHUSETTS EYE AND EAR INFIRMARY · 2024 · $640,774

## Abstract

Project Summary/Abstract
The long-term goals of the proposed research are to identify the genetic causes of inherited retinal
degenerations (IRDs), define the mechanisms by which mutations in IRD disease genes lead to retinal
degeneration, and to use this information to develop effective therapies to prevent vision loss from these
blinding disorders. IRDs are important causes of vision loss that affect people across the age spectrum. While
great progress has been made identifying the genetic causes of IRDs, approximately 1/3rd of patients have
genetic causality that remains elusive. Further, the mechanisms by which mutations in specific IRD disease
genes cause retinal degeneration remain to be defined for the majority of IRD disease genes. Identifying the
genetic causes of IRDs and the mechanisms of disease pathogenesis has become especially important as
genetic therapies such as gene augmentation therapy and neuroprotective therapies show great promise for
the treatment of IRDs. But several challenges remain to be addressed to succeed with broad application of
genetically informed therapies for IRDs. These include the need to define genetic causality for the 1/3rd of
patients with elusive genetic causes of disease, and the need to more completely define the cellular
mechanisms that connect mutations in a given gene with photoreceptor and RPE degeneration. The goal of
Aim 1 is to address the first of these challenges. Evidence suggests that the majority of IRD disease genes
have been identified, leading to the hypothesis that much of the missing genetic causality in the 1/3rd of IRD
patients resides in the non-coding portions of the currently known IRD disease genes. It is challenging,
however, to determine which of the 100s of rare deep intronic variants identified by whole genome sequencing
(WGS) in IRD genes in patients with IRDs are pathogenic. In Aim 1 a novel high throughput splicing assay
(HTSA) will be used to empirically test the functional effects of rare deep intronic variants identified in patients
with IRDs and to prospectively characterize rare deep intronic variants in actionable IRD genes. The goal of
Aim 2 is to address the second challenge by studying the mechanisms by which mutations in NMNAT1 cause
severe early onset IRD. Despite being required for nuclear NAD+ synthesis in all cells, reduced NMNAT1
function causes retina-specific disease in most patients. Data from studies using a mouse model of NMNAT1-
associated disease suggest that photoreceptor cells have the greatest demand for DNA repair of any cells in
the human body and thus are the most vulnerable to reduced NMNAT1 function. To identify the source(s) of
the DNA damage that underlie this high demand for DNA repair in photoreceptor cells the DNA modifications
that accumulate and the DNA damage response pathways that are activated in mouse and human models of
NMNAT1-associated disease will be studied in Aim 2. The results of these studies could inform development
of add...

## Key facts

- **NIH application ID:** 10899586
- **Project number:** 5R01EY012910-27
- **Recipient organization:** MASSACHUSETTS EYE AND EAR INFIRMARY
- **Principal Investigator:** Eric A Pierce
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $640,774
- **Award type:** 5
- **Project period:** 1999-07-08 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899586

## Citation

> US National Institutes of Health, RePORTER application 10899586, Precision Medicine for Inherited Retinal Degenerations (5R01EY012910-27). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10899586. Licensed CC0.

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