Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G
Year: 2017
Type: article
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.
Authors: Alice Emptoz, Vincent Michel, Andrea Lelli, Omar Akil, Jacques Boutet de Monvel, Ghizlene Lahlou, Anaïs Meyer, Typhaine Dupont, Sylvie Nouaille, Elody Ey, Filipa Franca de Barros, Mathieu Beraneck, Didier Dulon, Jean-Pierre Hardelin, Lawrence Lustig, Paul Avan, Christine Petit, Saaid Safieddine
Institutions: Inserm, Institut Pasteur, Sorbonne Université, Université Pierre-et-Marie-Curie, Institut de l'Audition, University of California, San Francisco, Centre National de la Recherche Scientifique, Gènes, synapses et cognition, Centre de Neurophysique Physiologie et Pathologie, Université Paris Descartes, Université de Bordeaux, NewYork–Presbyterian Hospital, Columbia University Irving Medical Center, Columbia University, Université Clermont Auvergne, Centre Jean Perrin, Université de Clermont I, Collège de France
Language: English
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $1,004
Awards: G1847873635, Restoration of hearing and balance in mouse model for human deafness and balance defects using gene therapy, G4031799020, G5551520971, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER, Sorbonne Universités à Paris pour l'Enseignement et la Recherche, G7240651115, DES SENS POUR TOUTE LA VIE, Fighting blindness of Usher syndrome: diagnosis, pathogenesis and retinal treatment (TreatRetUsher)
OpenAlex ID: W2746713428