# Precision Medicine for Inherited Retinal Degenerations

> **NIH NIH R01** · MASSACHUSETTS EYE AND EAR INFIRMARY · 2020 · $663,274

## Abstract

Project Summary/Abstract
The longterm goals of the proposed research are to help define the genetic causality of inherited retinal
degenerations (IRDs), improve our understanding of disease mechanisms, and develop effective gene and
genetically directed therapies for these disorders. IRDs are important causes of blindness that are characterized
by progressive dysfunction and death of the photoreceptor cells of the retina. Over 260 different types of IRDs
have been identified across all age groups by clinical and genetic studies, but the specific genetic cause remains
elusive in approximately one third of IRD patients. Further, the mechanisms by which identified mutations cause
vision loss remain to be defined for many forms of IRD. Identifying the genetic cause of patients’ IRD has
become especially important with the recent success of clinical trials of gene therapy for RPE65-associated
retinal degeneration. Further, studies in animal models have reported success of gene therapy for multiple
additional genetic types of IRD, leading to clinical trials for several other genetic forms of IRD. There is thus an
unprecedented opportunity to translate research progress into sight preserving treatment for patients with IRDs.
The goal of the proposed research is to capitalize on this opportunity via a set of integrated Aims focused on
identification of additional novel genetic causality of IRDs, including new disease genes and non-coding
mutations, and development of gene and genetic therapies for one form of IRD. In Aim 1, the genetic and
functional studies needed to evaluate candidate disease genes identified through whole exome sequencing
(WES) of families and cohorts of patients with IRDs will be performed. The applicant is part of the Joint Center
for Mendelian Genomics at the Broad Institute, via which the WES for these studies is being performed. In
addition to novel disease genes, data suggest that much of the missing genetic causality for IRDs is due to non-
coding mutations and structural variants (SVs) in known and potentially novel IRD disease genes. In Aim 2,
whole genome sequencing (WGS) and transcriptome analyses will be used to search for novel non-coding
genetic causality of IRDs in families with previously elusive genetic causes of disease. To build on the
understanding gained by helping define the genetic causality of IRDs, the mechanisms by which mutations in the
NMNAT1 gene cause retinal cell death and potential therapies for NMNAT1-associated disease will be studied in
Aim 3. The NMNAT1 enzyme is required for nuclear NAD+ synthesis, and is widely expressed. Based on data
obtained to date, it is hypothesized that by disrupting NAD+ homeostasis, mutations in NMNAT1 predispose cells
to death via parthanatos, a cell death mechanism involved in other forms of neurodegeneration. It is further
hypothesized that since retinal cells are highly metabolically active and sensitive to oxidative stress, they are
more susceptible to parthanatos in...

## Key facts

- **NIH application ID:** 10016305
- **Project number:** 5R01EY012910-23
- **Recipient organization:** MASSACHUSETTS EYE AND EAR INFIRMARY
- **Principal Investigator:** Eric A Pierce
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $663,274
- **Award type:** 5
- **Project period:** 1999-07-08 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10016305

## Citation

> US National Institutes of Health, RePORTER application 10016305, Precision Medicine for Inherited Retinal Degenerations (5R01EY012910-23). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10016305. Licensed CC0.

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