# Gene Therapy for Hearing and Balance Disorders

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2022 · $423,036

## Abstract

Project Summary
This project will develop a gene therapy strategy to treat hearing loss associated with Usher Syndrome type 3A
(USH3A) in human. This will involve optimizing viral vectors in mouse models of USH3A, testing the best
vectors for efficacy and cochlear toxicity in non-human primates and in human hair cells, and testing sequence
variants in the human USH3A gene (CLRN1) for pathogenicity. At the completion of the project, we will be
able to request a pre-IND meeting with the Food and Drug Administration to determine specific requirements
for preclinical testing.
Aim 1 is to test different AAV vectors for gene delivery to cochlear hair cells in mouse. Three new AAV-
related vectors have shown promise in transducing cochlear hair cells, and we will test them all to identify the
best. We will then test AAV-mediated restoration of hair cell function in the Clrn1-/- and N48K mouse models.
Finally, we will test toxicity to hearing of AAV-mediated Clrn1 expression.
Aim 2 is to test the efficacy of novel AAV vectors in human hair cells in vitro, and to test, in non-human
primates, the efficiency, toxicity and immunogenicity of these vectors administered by round window
membrane injection. We will test the two best vectors from Aim 1, expressing GFP to assess the degree of viral
transduction of hair cells. We will also describe toxicity and systemic distribution of GFP- and CLRN1-
encoding AAV vectors. An immune response might interfere with subsequent AAV injections or could lead to
toxicity in the inner ear, so we will determine whether AAV injection into the ear induces neutralizing
antibody or T-cell response.
In Aim 3 we will characterize human pre-existing immunity against applicable serotypes in perilymph, using
perilymph collected during surgery for other auditory disorders. We will also determine whether there is a
correlation between antibody titers in perilymph and serum. Many variants have been identified in the
CLRN1 gene but not all are known to be pathogenic. To determine which variants in CLRN1 in USH3A
patients are pathogenic, we will set up a complementation assay using the Clrn1-/- mouse, use AAV to express
Clrn1 with specific mutations equivalent to human variants of unknown significance, and assess degree of
functional rescue with electrophysiology and electron microscopy.

## Key facts

- **NIH application ID:** 10460137
- **Project number:** 5R01DC016932-05
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** DAVID P COREY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $423,036
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10460137

## Citation

> US National Institutes of Health, RePORTER application 10460137, Gene Therapy for Hearing and Balance Disorders (5R01DC016932-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10460137. Licensed CC0.

---

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