# Genetic Strategies for the Treatment of Usher Syndrome in Mice

> **NIH NIH F30** · LSU HEALTH SCIENCES CENTER · 2021 · $37,889

## Abstract

Abstract
Usher syndrome (Usher) is the leading inherited cause of combined deafness and blindness, affecting as many
as 1 in 6000 in the general U.S. population. Type 1 Usher, the most severe form, is characterized by vestibular
dysfunction and profound hearing impairment at birth followed by retinitis pigmentosa (RP) beginning in early
adolescence. Worldwide, 2.5% of Usher cases are caused by mutations in the USH1C gene, which encodes
harmonin. Previously, our laboratory created a knock-in mouse model containing the USH1C c.216G>A splicing
mutation (216A) which is responsible for Usher Type 1C (USH1C) in the Acadian populations in the U.S. and
Canada. Antisense oligonucleotides (ASOs) designed to target the 216A mutation block the aberrant splice site
and improve Ush1c RNA splicing. Treatment of USH1C mice with ASOs improves the expression of full-length
harmonin protein in the cochlea and retina with an increase in vestibular, auditory, and visual function
comparable to wild type mice. These improvements are sustained for at least 1 year with additional treatments.
Despite improvements, the underlying pathophysiological mechanisms by which the mutant Ush1c gene
contributes to these clinical phenotypes, along with the mechanisms by which rescue of the mutant phenotype
reverses visual impairment, remain largely unknown. Therefore, we hypothesize that RP functional
impairments and underlying retinal defects associated with the USH1C c.216G>A mutation are caused
by the loss of functional harmonin. This hypothesis will be tested in two Specific Aims: (1) test the prediction
that Ush1c gene replacement therapy will restore harmonin levels in photoreceptor cells and correct RP in
USH1C mice; and (2) test the prediction that genome editing of the 216A mutation via clustered regularly-
interspaced short palindromic repeats (CRISPR)/Cas9 system will restore endogenous expression of harmonin
in photoreceptor cells and correct RP in USH1C mice. Transgenic USH1C mice will be treated by subretinal
injections of either Ush1c gene-expressing viral vectors or CRISPR/Cas9 genome-editing system at different
ages. Ush1c transcript and harmonin protein expression will be measured using RT-PCR and western blot
analysis, respectively. Optical coherence tomography (OCT) will be used to assess retinal integrity before and
after treatments. Harmonin protein expression and localization in the retina will be measured by
immunohistochemistry. Visual function will be assessed using electroretinography (ERG) analysis, and gross
visual ability will be assessed using a visual cliff behavioral test. The research completed in both Aims will
contribute to the development of a novel, one-time treatment regimen for correcting RP in USH1C. Molecular
and structural analyses completed through the proposed research project will provide insight into loss or gain of
function mechanisms caused by the USH1C c.216G>A mutation, which will help us to achieve our long-term
goal of developing t...

## Key facts

- **NIH application ID:** 10167713
- **Project number:** 5F30EY028009-04
- **Recipient organization:** LSU HEALTH SCIENCES CENTER
- **Principal Investigator:** Katelyn N Robillard
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $37,889
- **Award type:** 5
- **Project period:** 2018-06-05 → 2022-06-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167713

## Citation

> US National Institutes of Health, RePORTER application 10167713, Genetic Strategies for the Treatment of Usher Syndrome in Mice (5F30EY028009-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10167713. Licensed CC0.

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