# CLARIN 1 RETINAL FUNCTION AND THERAPEUTIC IMPLICATIONS FOR USH3

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $375,000

## Abstract

ABSTRACT
Usher syndrome (USH) is an inherited disorder responsible for more than half of combined deafness and
blindness in humans. It affects both photoreceptors and cochlear hair cells, the sensory neurons of the
retina and inner ear, respectively. Usher syndrome type III (USH3) is caused by mutations in clarin-1
(CLRN1) gene, leading to the gradual and permanent loss of both vision and normal hearing. Cochlear
implantation alleviates to some degree the hearing impairment, but there is no treatment that prevents the
progressive photoreceptor cell death that leads to blindness. Our goal is to develop an understanding of
CLRN1 function in the retina so that a rational gene therapy approach for USH3 patients can be developed.
Efforts to identify efficient therapeutic strategies for vision loss are hindered by the lack of USH3 animal
models that mimic the human retinal disorder, and by conflicting reports on CLRN1’s endogenous cellular
localization, with only one study showing its presence in photoreceptors. All current USH3 mouse models
display a rapid hearing loss but normal retinal function and morphology. As part of a collaborative effort, we
showed that CLRN1 gene replacement therapy using adeno-associated viral vectors (AAVs) can prevent
hearing loss for at least 1 year following cochlear delivery in a mouse model of USH3, the first successful
proof of concept experiment for this disorder. We also showed that retinal function is preserved following a
similar gene therapy approach to treat the retina in a new mouse model of USH3, which displays a slow,
progressive loss of retinal function with aging. These results suggest that postnatal CLRN1 delivery can
prevent further loss of function in sensory cells, a particularly relevant issue for patients with more advanced
stages of disease. Our central hypothesis is that CLRN1 plays an essential role in photoreceptor cells,
structurally stabilizing the fragile connecting cilium region by interacting with other USH proteins and
cytoskeletal elements. We address this hypothesis with three specific aims: 1) identify CLRN1’s
endogenous retinal localization and the proteins that interact with CLRN1 in the mouse retina; 2) determine
the retinal expression pattern and pathogenic effects of mutant CLRN1 proteins in-vivo; 3) test several gene
therapy options in USH3 mouse models, targeting either the entire retina, or the photoreceptors alone.
Completion of these goals would firmly identify CLRN1’s general function and, critically, serve to pinpoint
which cells would need to be targeted for USH3 gene replacement therapy to prevent the loss of vision in
patients.

## Key facts

- **NIH application ID:** 10006553
- **Project number:** 5R01EY026559-05
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** ASTRA DINCULESCU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $375,000
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006553

## Citation

> US National Institutes of Health, RePORTER application 10006553, CLARIN 1 RETINAL FUNCTION AND THERAPEUTIC IMPLICATIONS FOR USH3 (5R01EY026559-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10006553. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*