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Molecular pathology of cochlear gap junction in GJB2 associated hearing loss

Presenting Author: Kazusaku Kamiya

Published online by Cambridge University Press:  03 June 2016

Kazusaku Kamiya ,
Ichiro Fukunaga  and
Katsuhisa Ikeda
Kazusaku Kamiya
Affiliation:
Juntendo University Faculty of Medicine
Ichiro Fukunaga
Affiliation:
Juntendo University Faculty of Medicine
Katsuhisa Ikeda
Affiliation:
Juntendo University Faculty of Medicine
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Abstract

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Learning Objectives:

Introduction: Hereditary deafness affects about 1 in 2000 children and GJB2 gene mutation is most frequent cause for this disease. GJB2 encodes connexin (Cx) 26, a component in cochlear gap junction. We recently demonstrated that the drastic disruption of gap junction plaque (GJP) macromolecular complex composed of Cx26 and Cx30 are critical pathogenesis starting before hearing onset (Kamiya et al., 2014, J Clin Invest 124, 1598–1607). To develop the effective therapy for GJB2 associated hearing loss, restoration of gap junction plaque (GJP) macromolecular complex using virus vectors or multipotent stem cells such as induced prulipotent stem (iPS) cells and mescenchimal stem cell (MSC) are expected to rescue the hearing function of GJB2 related hearing loss.

Methods: Mouse induced pluripotent stem cells (iPS) were used for generation of Cx26-expressing cells with proper gap junction plaque between the cells. Adeno associate virus (AAV) were used for the GJB2 gene transfer and restoration of GJP.

Results: By diffentiation of iPS cells, we generated the Cx26-expressiong cells with large gap junction plaque as cochlear cells. Cochlear delivery of Gjb2 using AAV significantly improved the auditory responses and development of the cochlear structure of Cx26f/fP0Cre mice (Iizuka, Hum Mol Genet, 2015, 24(13):3651–61).

Conclusions: Using cell therapy or gene therapy to restore hearing in the mouse models of Gjb2-related deafness may lead to the development of effective therapies for human hereditary deafness.