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Proc Natl Acad Sci U S A. 2017 Sep 5;114(36):9695-9700. doi: 10.1073/pnas.1708894114. Epub 2017 Aug 23.

Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G.

Author information

1
INSERM, UMR 1120, Paris, France.
2
Génétique et Physiologie de l'Audition, Institut Pasteur, 75015 Paris, France.
3
Complexité du Vivant, Sorbonne Universités, Université Pierre-et-Marie-Curie, Université Paris VI, 75015 Paris, France.
4
Otolaryngology-Head & Neck Surgery, University of California, San Francisco, CA 94117.
5
Unité de Génétique Humaine et Fonctions Cognitives, Institut Pasteur, CNRS UMR 3571, 75015 Paris, France.
6
Centre de Neurophysique, Physiologie, et Pathologie, CNRS UMR 8119, Université Paris-Descartes, 75006 Paris, France.
7
Laboratoire de Neurophysiologie de la Synapse Auditive, Bordeaux Neurocampus, INSERM, UMR 1120, Université de Bordeaux, 33076 Bordeaux, France.
8
Columbia University School of Medicine and New York Presbyterian Hospital, New York, NY 10034.
9
Laboratoire de Biophysique Sensorielle, Faculté de Médecine, Université d'Auvergne, Biophysique Médicale, Centre Jean Perrin, 63000 Clermont-Ferrand, France.
10
INSERM, UMR 1120, Paris, France; christine.petit@pasteur.fr saaid.safieddine@pasteur.fr.
11
Collège de France, 75005 Paris, France.

Abstract

Our understanding of the mechanisms underlying inherited forms of inner ear deficits has considerably improved during the past 20 y, but we are still far from curative treatments. We investigated gene replacement as a strategy for restoring inner ear functions in a mouse model of Usher syndrome type 1G, characterized by congenital profound deafness and balance disorders. These mice lack the scaffold protein sans, which is involved both in the morphogenesis of the stereociliary bundle, the sensory antenna of inner ear hair cells, and in the mechanoelectrical transduction process. We show that a single delivery of the sans cDNA by the adenoassociated virus 8 to the inner ear of newborn mutant mice reestablishes the expression and targeting of the protein to the tips of stereocilia. The therapeutic gene restores the architecture and mechanosensitivity of stereociliary bundles, improves hearing thresholds, and durably rescues these mice from the balance defects. Our results open up new perspectives for efficient gene therapy of cochlear and vestibular disorders by showing that even severe dysmorphogenesis of stereociliary bundles can be corrected.

KEYWORDS:

Usher; balance; gene; mouse; therapy

PMID:
28835534
PMCID:
PMC5594693
DOI:
10.1073/pnas.1708894114
[Indexed for MEDLINE]
Free PMC Article

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