Outer Hair Cell Gene Editing Ameliorates Progressive Hearing Loss in Dominant-negative Murine Model

Overview

Journal Theranostics

Date 2022 Mar 10

PMID 35265220

Authors

Byunghwa Noh

John Hoon Rim

Ramu Gopalappa

Haiyue Lin

Kyu Min Kim

Min Jin Kang

Heon Yung Gee

Jae Young Choi

Hyongbum Henry Kim

Jinsei Jung

Affiliations

Soon will be listed here.

Abstract

Outer hair cell (OHC) degeneration is a major cause of progressive hearing loss and presbycusis. Despite the high prevalence of these disorders, targeted therapy is currently not available. We generated a mouse model harboring to recapitulate DFNA2, a common genetic form of progressive hearing loss accompanied by OHC degeneration. After comprehensive optimization of guide RNAs, Cas9s, vehicles, and delivery routes, we applied gene editing strategy to disrupt the dominant-negative allele in and prevent progressive hearing loss. gene editing using a dual adeno-associated virus package targeting OHCs significantly improved auditory thresholds in auditory brainstem response and distortion-product otoacoustic emission. In addition, we developed a new live-cell imaging technique using thallium ions to investigate the membrane potential of OHCs and successfully demonstrated that mutant allele disruption resulted in more hyperpolarized OHCs, indicating elevated KCNQ4 channel activity. These findings can facilitate the development of targeted therapies for DFNA2 and support the use of CRISPR-based gene therapy to rectify defects in OHCs.

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