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

EMBO Molecular Medicine

Qing Chang¹  Jianjun Wang¹  Qi Li¹  Yeunjung Kim¹  Binfei Zhou¹  Yunfeng Wang²  Huawei Li² 

[1] Department of Otolaryngology, Emory University School of Medicine, Atlanta, GA, USA;Department of Otolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China

关键词: gene therapy;    hearing restoration;    Jervell and Lange‐Nielsen syndrome;    Kcnq1 null mice;    virus;   

DOI  :  10.15252/emmm.201404929

来源: Wiley

【 摘 要 】

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.

Synopsis

First gene replacement therapy proof of principle for a deafness gene defect (Kcnq1) affecting the stria vascularis, a major site affected by genetic mutations in inherited hearing loss cases.

• Gene therapy to preserve hearing was tested in a mouse model of Jervell and Lange-Nielsen syndrome (Kcnq1^−/− mice).
• Extensive ectopic virally mediated Kcnq1 transgene expression did not affect normal cochlear functions.
• Cochlear morphological data, normal endocochlear potential, and significant hearing preservation after treatment demonstrated phenotypic correction.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

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