# Autosomal Dominant Non-Syndromic Hearing Loss - Its Genetic Diagnosis and Treatment

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2021 · $486,171

## Abstract

Project Summary
 Hearing loss affects 15-26% of the world's population. Amongst the elderly, it ranks as the most common
neurological disability, impacting ~50% of octogenarians. The majority of inherited late-onset deafness is
autosomal dominant and non-syndromic. In this new porposal, we will build on our experience and expertise in
human genetics and gene therapy to improve genetic deafness for deafness by leveraging the power of single-
cell RNA sequencing and to establish whether targeted allele suppression can prevent or potentially reverse
hearing loss in mature animal models of human deafness by using RNA interference (RNAi).
 To achieve these goals, we propose the following specific aims:
• Specific Aim 1. Using single-cell isolation techniques, we propose:
 o SA1A. To refine our knowledge of individual cell-specific transcription in the organ of Corti and improve
 comprehensive genetic testing for deafness by identifying and characterizing novel exons and isoforms
 of genes implicated in both non-syndromic and syndromic forms of hearing loss.
 o SA1B. To characterize the broader impact of single gene mutations on the transcriptome of individual
 cells in two murine models of human ADNSHL – the Kncq4+/- mouse, which is a model of human
 DFNA2-related hearing loss, and the Tmc1Bth/+ mouse (the Beethoven (Bth) mouse), which is a model of
 human DFNA36-related hearing loss.
• Specific Aim 2. Using RNAi, we propose:
 o SA2A. To establish whether targeted allele suppression can prevent or potentially reverse hearing loss
 in mature animals.
 o SA2B. To develop a broadly applicable treatment strategy for all types of deafness caused by a single
 gene using a novel RNAi construct that suppresses both endogenous alleles with concomitant gene
 replacement by an exogenous wild-type allele engineered to resist RNAi-mediated silencing.
 o SA2C. To determine whether systemic neutralizing antibodies (NAbs) to AAV impact the transduction
 efficiency of AAV-mediated cochlear gene therapy.
 The successful completion of these aims will advance our understanding of the biology of hearing and
deafness, enhance the clinical care of persons with hearing loss, and potentially lay the foundation for clinical
trials using RNAi as a treatment option for some types of hearing loss.

## Key facts

- **NIH application ID:** 10200758
- **Project number:** 5R01DC017955-03
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Richard J.H. Smith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $486,171
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200758

## Citation

> US National Institutes of Health, RePORTER application 10200758, Autosomal Dominant Non-Syndromic Hearing Loss - Its Genetic Diagnosis and Treatment (5R01DC017955-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10200758. Licensed CC0.

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