# Improving the throughput of diagnosis and treatment of inherited diseases of the retina

> **NIH NIH R01** · MASSACHUSETTS EYE AND EAR INFIRMARY · 2021 · $412,250

## Abstract

Project Summary/Abstract
Despite advances in genetic testing for inherited retinal degenerations (IRDs), detection of a DNA variant of
unknown significance (VUS) can prevent a patient from receiving a genetic diagnosis. The long-term goal of the
proposed research is to address this problem using cell-based assays that can efficiently identify which DNA
variants are disease-causing mutations and which are benign polymorphisms, at a scale that would produce
medically-actionable information. IRDs are important causes of vision loss, and are increasingly treatable by
gene-specific therapies such as gene augmentation therapy. While an accurate genetic diagnosis is critical
before administering a gene-specific therapy, confident identification of the genetic cause for particular patient’s
IRD can be difficult, with about one third of patients failing to receive a genetic diagnosis altogether. Thus, there
is an unprecedented need to efficiently identify the genetic causality of IRDs in order to translate existing and
emerging sight-preserving or sight-restoring therapies to patients. To address this need, the goal of the proposed
research is to capitalize on this opportunity via a set of integrated Aims focused on the efficient identification of
pathogenic variants in important IRD genes. The proposed research seeks to shift the current research
paradigm-- analyzing small numbers of DNA variants in IRD genes as they are discovered-- to a paradigm
where large quantities of data are generated in advance about variants in medically-important IRD genes.
Therefore, the proposed research tests the hypothesis that empiric, cell-based assays can be used to efficiently
and accurately identify which DNA variants in humans are pathogenic and cause IRDs, and which are likely
benign polymorphisms. In Aim 1, we assemble and characterize a comprehensive collection of potentially
pathogenic amino acid changes in an important dominant IRD gene, rhodopsin. An expansion of this Aim tests
which of these mutations are amenable to chaperone therapy with small molecules. In Aim 2, these techniques
are modified to characterize a comprehensive collection of potentially pathogenic amino acid changes in an
important recessive IRD gene, RPE65. It is further hypothesized that comparing assay results to human
phenotype data will define proper numerical ranges which correspond to pathogenic results in humans. Viewed
together, these Aims provide a pathway for producing an openly-available resource that could instantly provide
higher-fidelity information about VUS in IRDs to medical geneticist, genetic counselors, and investigators of
IRDs. It takes advantage of a significant opportunity where investigation of the Aims can directly produce
medically-actionable information resulting in the delivery of therapies to otherwise untreatable patients.

## Key facts

- **NIH application ID:** 10228094
- **Project number:** 5R01EY031036-02
- **Recipient organization:** MASSACHUSETTS EYE AND EAR INFIRMARY
- **Principal Investigator:** Jason Comander
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $412,250
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10228094

## Citation

> US National Institutes of Health, RePORTER application 10228094, Improving the throughput of diagnosis and treatment of inherited diseases of the retina (5R01EY031036-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10228094. Licensed CC0.

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