# Development of CRISPR/Cas9-based exon-skipping strategies for the treatment of USH-associated deafness

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2023 · $695,726

## Abstract

Abstract: Usher syndrome (USH) is the most common form of inherited deaf-blindness, with a prevalence of 1/6.000.
Inherited as an autosomal recessive trait, it affects about 15,000 people in the United States and is responsible for 6% of
early childhood deafness. Usher syndrome is classified under three clinical subtypes (USH-1, -2 and -3) according to the
severity of the symptoms. Approximately 2/3 of the patients with USH suffer from USH2 and USH1, of whom 75% have
mutations in the USH2A, USH1D and 1F genes. Because USH affects both major senses, it is a severely debilitating
condition, and intense research is crucial to improve coping strategies and develop therapies for the patients. It is particularly
devastating during the current pandemic, with social distancing and the wearing of masks making communication nearly
impossible. Treatment for USH is limited to cochlear implants, and there is no treatment for the blindness. Development of
an effective therapeutic approach for USH has been challenging due to the large size of USH genes. Therefore, there is an
unmet need to develop alternative therapeutic strategies. The goal of this project is to develop and test novel therapy
approaches for treating recessive deafness in human hair cells of inner ear organoids derived from human induced
pluripotent stem cells (hiPSCs) and in USH mouse models by establishing genome editing-based therapeutic strategies for
USH and to lay the foundation for moving genome editing approaches closer clinical trials. We have chosen to focus on
the most common mutations in the three major USH genes with the following reasons: 1) The USH2A, 1D, and 1F genes
are the most common and important USH genes which are responsible for more than 70% human USH cases with significant
clinical application; 2) Due to their large size, traditional gene augmentation or addition therapy is hampered as its coding
sequence far exceeds the packaging capacity of standard gene therapy vectors; 3) All three USH2A, 1D, and 1F genes
contain similar multiple repetitive domains with in frame common mutations in their protein structures, making them
potential targets for exon-skipping-based therapies (see Preliminary data); 4) We have obtained exciting data demonstrating
restoration of hearing in an Ush2a mouse model using exon skipping strategy with an available mouse model of USH2A
and have successfully generated hiPSCs from Usher patients carrying the most common mutations of USH, and established
optimized protocols for generation of large numbers of human inner ear organoids with the production of human hair cells
derived from these hiPSCs. This proposal leverages the exceptional deafness genomics information and genome editing
expertise of collaborators for the development of novel treatments for HL. In this proposal, we will build on our
accomplishments and preliminary data by proposing to complete the following specific aims: 1) to develop CRISPR/Cas9-
based exon-skipping strategies to res...

## Key facts

- **NIH application ID:** 10688070
- **Project number:** 5R01DC019404-02
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Zheng-Yi Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $695,726
- **Award type:** 5
- **Project period:** 2022-08-22 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10688070

## Citation

> US National Institutes of Health, RePORTER application 10688070, Development of CRISPR/Cas9-based exon-skipping strategies for the treatment of USH-associated deafness (5R01DC019404-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10688070. Licensed CC0.

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