Targeted Allele Suppression Prevents Progressive Hearing Loss in the Mature Murine Model of Human TMC1 Deafness

Hidekane Yoshimura; Seiji B Shibata; Paul T Ranum; Hideaki Moteki; Richard J.H Smith

doi:10.1016/j.ymthe.2018.12.014

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Targeted Allele Suppression Prevents Progressive Hearing Loss in the Mature Murine Model of Human TMC1 Deafness

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Targeted Allele Suppression Prevents Progressive Hearing Loss in the Mature Murine Model of Human TMC1 Deafness

Hidekane Yoshimura, Seiji B Shibata, Paul T Ranum, Hideaki Moteki and Richard J.H Smith

Molecular therapy, Vol.27(3), pp.681-690

03/06/2019

DOI: 10.1016/j.ymthe.2018.12.014

PMCID: PMC6403483

PMID: 30686588

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Abstract

Hearing loss is the most common human sensory deficit. Its correction has been the goal of several gene-therapy based studies exploring a variety of interventions. Although these studies report varying degrees of success, all treatments have targeted developing inner ears in neonatal mice, a time point in the structural maturation of the cochlea prior to 26 weeks gestational age in humans. It is unclear whether cochlear gene therapy can salvage hearing in the mature organ of Corti. Herein, we report the first study to test gene therapy in an adult murine model of human deafness. Using a single intracochlear injection of an artificial microRNA carried in an AAV vector, we show that RNAi-mediated gene silencing can slow progression of hearing loss, improve inner hair cell survival, and prevent stereocilia bundle degeneration in the mature Beethoven mouse, a model of human TMC1 deafness. The ability to study gene therapy in mature murine ears constitutes a significant step toward its translation to human subjects. Smith and colleagues demonstrate the effect of cochlear gene therapy in an adult murine model of human TMC1 deafness and show that RNAi-mediated gene silencing slows progression of hearing loss, suggesting a significant step toward its application in human subjects.

adeno-associated virus

cochlea

gene therapy

hearing loss

inner ear

vestibule

Details

Title: Subtitle: Targeted Allele Suppression Prevents Progressive Hearing Loss in the Mature Murine Model of Human TMC1 Deafness
Creators: Hidekane Yoshimura - Shinshu University
Seiji B Shibata - Roy J. and Lucille A. Carver College of Medicine
Paul T Ranum - University of Iowa
Hideaki Moteki - Shinshu University
Richard J.H Smith - Roy J. and Lucille A. Carver College of Medicine
Resource Type: Journal article
Publication Details: Molecular therapy, Vol.27(3), pp.681-690
DOI: 10.1016/j.ymthe.2018.12.014
PMID: 30686588
PMCID: PMC6403483
NLM abbreviation: Mol Ther
ISSN: 1525-0016
eISSN: 1525-0024
Publisher: Elsevier Inc
Grant note: name: NIH/NIDCD, award: T32 DC000040-17, R01 DC03544; name: AAO-HNSF Resident Research Grant 2013
Language: English
Date published: 03/06/2019
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
Record Identifier: 9984256925902771

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