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Author Notes:

Email Address: Huawei Li :hwli@shmu.edu.cn ; Xi Lin :xlin2@emory.edu

QC and JW conducted and designed part of the experiments, analyzed a subset of data, and wrote part of the paper.

QL, YK and YW conducted part of the experiments and analyzed a subset of data.

BZ conducted part of the experiments and maintained mouse breeding pairs.

HL designed part of the experiments, analyzed a subset of data, and wrote part of the paper.

XL conducted and designed all the experiments, analyzed data, and wrote the paper.

We thank Ms. Anne Lin for proofreading the manuscript.

The authors declare that they have no conflict of interest.

Subjects:

Research Funding:

This study was supported by grants to XL from the National Institute on Deafness and other Communication Disorders (RO1 DC006483 and RO1 DC010204).

Huawei Li received grant support from the National Science Foundation of China (#30728029 and #81230019) and the 973 Program (2011CB504506).

Lin and Li also received grant support from the National Science Foundation of China (30728029).

Keywords:

  • Jervell and Lange‐Nielsen syndrome
  • Kcnq1 null mice
  • gene therapy
  • hearing restoration
  • virus

Virally mediated Kcnq1 gene replacement therapy in the immature scala media restores hearing in a mouse model of human Jervell and Lange-Nielsen deafness syndrome

Tools:

Journal Title:

EMBO Molecular Medicine

Volume:

Volume 7, Number 8

Publisher:

, Pages 1077-1086

Type of Work:

Article | Final Publisher PDF

Abstract:

Mutations in the potassium channel subunit KCNQ1 cause the human severe congenital deafness Jervell and Lange-Nielsen (JLN) syndrome. We applied a gene therapy approach in a mouse model of JLN syndrome (Kcnq1−/− mice) to prevent the development of deafness in the adult stage. A modified adeno-associated virus construct carrying a Kcnq1 expression cassette was injected postnatally (P0–P2) into the endolymph, which resulted in Kcnq1 expression in most cochlear marginal cells where native Kcnq1 is exclusively expressed. We also found that extensive ectopic virally mediated Kcnq1 transgene expression did not affect normal cochlear functions. Examination of cochlear morphology showed that the collapse of the Reissner’s membrane and degeneration of hair cells (HCs) and cells in the spiral ganglia were corrected in Kcnq1−/− mice. Electrophysiological tests showed normal endocochlear potential in treated ears. In addition, auditory brainstem responses showed significant hearing preservation in the injected ears, ranging from 20 dB improvement to complete correction of the deafness phenotype. Our results demonstrate the first successful gene therapy treatment for gene defects specifically affecting the function of the stria vascularis, which is a major site affected by genetic mutations in inherited hearing loss.

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© 2015 The Authors.

This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits making multiple copies, distribution, public display, and publicly performance, distribution of derivative works, provided the original work is properly cited. This license requires copyright and license notices be kept intact, credit be given to copyright holder and/or author.

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