# Generation and Characterization of Novel Large Animal Models of Usher Syndrome Type 3

> **NIH NIH R21** · UNIVERSITY OF FLORIDA · 2023 · $192,577

## Abstract

Project Summary/Abstract
Usher syndrome type 3 (USH3) is an autosomal recessive disorder caused by mutations in the Clarin-1 (CLRN1)
gene. It is a devastating disease, leading to retinal degeneration and progressive hearing loss, with variable
vestibular dysfunction. USH3 is considered an orphan disease, accounting for approximately 2% of all USH
cases. Currently, there are no therapeutic approaches to prevent vision loss caused by the death of light-sensing
retinal photoreceptors. Cochlear implantation alleviates the hearing loss by stimulating the auditory nerve
directly, and bypassing the damaged hair cells in the inner ear. However, the long-term effectiveness of this
approach is currently unknown. Thus, there is a critical unmet need to develop therapeutic strategies for both
the retinal and cochlear USH3 phenotypes. In our recently published study, we took a single-cell RNA
sequencing approach (scRNAseq), combined with in-situ hybridization assays, and found that CLRN1 transcripts
are confined to the inner retina, and are enriched in Müller glia in three distinct species, human, mouse and non-
human primates. This novel view of Müller glia-centered disease highlights the role of this important cell-type in
future therapeutic studies to prevent vision loss in USH3. However, currently available genetically engineered
mouse models of USH3 (lacking CLRN1) maintain normal vision (no degeneration) throughout their lifespan
despite undergoing rapid hearing loss and profound deafness by 1 month of age. The lack of an animal model
that mimics the human USH3 ocular disease is a major barrier in the field. It prevents us from understanding the
disease mechanisms and from evaluating the efficacy of therapeutic approaches to prevent blindness in USH3.
This R21 proposal aims to fill this critical need by creating a large animal model of USH3 that recapitulates the
human phenotype. Toward this goal, we used CRISPR/Cas9 genome editing technology and successfully
generated founder USH3 pigs lacking the main CLRN1 isoform. In Specific Aim 1, we will continue to characterize
the natural history of disease onset and progression in biallelic founders, and create homozygous monoallelic
USH3 pigs. We will characterize the disease progression in all USH3 pigs with noninvasive approaches similar
to those used to diagnose and track patients in the clinic, including fundus imaging, full-field electroretinography
(ERG) and spectral-domain optical coherence tomography (SD-OCT) for longitudinal assessment of retinal
function and structure. In Specific Aim 2, we will determine the structural and molecular impact of CLRN1
absence on the retina in USH3 pigs by using comparative histological and transcriptomic analyses. An USH3
large animal model is urgently needed to overcome a major barrier in the field. It has a tremendous potential for
immediate significant impact on preventing blindness in USH3 patients and it should also be a resource for
studying/treating hearing los...

## Key facts

- **NIH application ID:** 10706969
- **Project number:** 5R21EY032575-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** ASTRA DINCULESCU
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $192,577
- **Award type:** 5
- **Project period:** 2022-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10706969

## Citation

> US National Institutes of Health, RePORTER application 10706969, Generation and Characterization of Novel Large Animal Models of Usher Syndrome Type 3 (5R21EY032575-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10706969. Licensed CC0.

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