# Mechanisms to Rescue Photoreceptors in GUCY2D and GUCA1A Retinopathies

> **NIH NIH R01** · DREXEL UNIVERSITY · 2024 · $374,832

## Abstract

PROJECT SUMMARY
A diverse group of autosomal-dominant mutations that cause human blindness as a result of rod and cone
degeneration includes multiple mutations in two genes, GUCY2D coding for retinal guanylyl cyclase 1
(RetGC1) and GUCA1A coding for guanylyl cyclase activating protein 1 (GCAP1). These mutations explicitly
trigger photoreceptor death via a common mechanism – by abnormally elevating cyclic GMP production in the
dark. Although the biochemical origin of the dominant GUCY2D and GUCA1A retinopathies became better
understood over the past decade, potential approaches to their therapy, such as using gene editing or RNA
interference to suppress particular alleles causing the disease, continue to present a major conceptual
challenge. This proposal, conforming to the NEI mission to support research with respect to blinding eye
diseases, visual disorders and mechanisms of visual function, explores the foundation of a new approach for
the prospective therapy – targeting the common biochemical pathway underlying GUCY2D and GUCA1A
dominant retinopathies. The proposal is built on the following main findings: (i) understanding that deregulation
of RetGC1 activity is the key to the photoreceptor death caused by the gain-of-function mutations in GUCY2D
and GUCA1A; (ii) development of mouse genetic models for studying the biochemical and physiological
mechanisms of degeneration incited by the mutant RetGC1 and GCAP1; (iii) recent findings that the abnormal
increase in cGMP production that leads to photoreceptor death can be effectively opposed by three different
biochemical processes, such as acceleration of cGMP decay in the dark by recombinant phosphodiesterase 5
(PDE5r), stemming RetGC1 activation by GCAP1 using a newly designed protein inhibitor of guanylyl cyclase
(PIGC), and enhancing protection of photoreceptors against the presence of deregulated RetGC1 using retinal
degeneration-3 (RD3) protein. The research plan of this proposal pursues three Specific Aims, each
addressing a new original concept designed to avert photoreceptor dystrophy caused by deregulation of
RetGC1. Specific Aim 1 explores the biochemical and physiological mechanisms underlying rescue of
photoreceptors in mouse models harboring the degenerative mutants of RetGC1 and GCAP1 using ectopic
expression of PDE5r. Aim 2 explores mechanisms of their rescue using PIGC. Aim 3 explores the mechanisms
supporting the survival of photoreceptors using RD3. We reason that achieving these Specific Aims will help in
developing approaches to the future therapy of the dominant GUCY2D and GUCA1A retinopathies.

## Key facts

- **NIH application ID:** 11160857
- **Project number:** 7R01EY034861-03
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** ALEXANDER M DIZHOOR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $374,832
- **Award type:** 7
- **Project period:** 2023-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11160857

## Citation

> US National Institutes of Health, RePORTER application 11160857, Mechanisms to Rescue Photoreceptors in GUCY2D and GUCA1A Retinopathies (7R01EY034861-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11160857. Licensed CC0.

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