Virally expressed connexin26 restores gap junction function in the cochlea of conditional Gjb2 knockout mice

• Type of Material: Article
• Authors: Qing Yu, Emory University; Yunfeng Wang, Fudan University; Qing Chang, Emory University; Jianjun Wang, Emory University; Shushen Gong, Capital Medical University; Huawei Li, Fudan University; Xi Erick Lin, Emory University
• Language: English
• Date: 2014-01
• Publisher: Gene Therapy Press
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Macmillan Publishers Limited. All rights reserved.
• Final Published Version (URL): http://www.nature.com/gt/journal/v21/n1/full/gt201359a.html
• Title of Journal or Parent Work: Gene Therapy and Molecular Biology
• Volume: 21
• Issue: 1
• Start Page: 71
• End Page: 80
• Grant/Funding Information: This study was supported by grants to Wang from the National Nature Science Foundation of China (81100721), and to Lin from National Institute on Deafness and other Communication Disorders (RO1 DC006483 and NIDCD 4R33DC010476).; Huawei Li also received grant support from the National Science Foundation of China (#30728029 and #81230019) and 973 program (2011CB504506).
• Keywords: deafness; Gjb2; cochlea; connexin26; hearing; scala media; gene therapy
• Research Categories: Health Sciences, Audiology; Biology, Genetics

Abstract

Mutations in GJB2, which codes for the gap junction protein connexin26, are the most common causes of human nonsyndromic hereditary deafness. We inoculated modified adeno-associated viral vectors into the scala media of early postnatal conditional Gjb2 knockout mice to drive exogenous connexin26 expression. We found extensive virally-expressed connexin26 in cells lining the scala media, and intercellular gap junction network was re-established in the organ of Corti of mutant mouse cochlea. Widespread ectopic connexin26 expression neither formed ectopic gap junctions nor affected normal hearing thresholds in wild type mice, suggesting that autonomous cellular mechanisms regulate proper membrane trafficking of exogenously-expressed connexin26 and govern the functional manifestation of them. Functional recovery of gap-junction-mediated coupling among the supporting cells was observed. We found that both cell death in the organ of Corti and degeneration of spiral ganglion neurons in the cochlea of mutant mice were substantially reduced, although auditory brainstem responses did not show significant hearing improvement. This is the first report demonstrating that virally-mediated gene therapy restored extensive gap junction intercellular network among cochlear non-sensory cells in vivo. Such a treatment performed at early postnatal stages resulted in a partial rescue of disease phenotypes in the cochlea of the mutant mice.