Journal Article

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

Petit, Christine, de Barros, Filipa Franca, Lahlou, Ghizlene, Michel, Vincent, Akil, Omar, Emptoz, Alice, Meyer, Anaïs, Nouaille, Sylvie, Hardelin, Jean-Pierre, Avan, Paul, Dulon, Didier, Lelli, Andrea, Beraneck, Mathieu, Lustig, Lawrence, Ey, Elody, Dupont, Typhaine, Safieddine, Saaid, de Monvel, Jacques Boutet

2017

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Animals / Animals, Newborn / Balance / Biological Sciences / Bundles / Bundling / Cochlea / Congenital diseases / Deafness / Dependovirus - genetics / Disease Models, Animal / Disorders / DNA, Complementary - administration & dosage / DNA, Complementary - genetics / Ear / Evoked Potentials, Auditory, Brain Stem / Gene therapy / Genetic Therapy - methods / Genetic Vectors / Hair cells / Hair Cells, Auditory - pathology / Hair Cells, Auditory - physiology / Hearing loss / Human health and pathology / Humans / Inner ear / Life Sciences / Medical Sciences / Mice / Mice, Knockout / Microscopy, Electron, Scanning / Morphogenesis / Nerve Tissue Proteins - deficiency / Nerve Tissue Proteins - genetics / Rodents / Sensory Organs / Signal transduction / Studies / Tips / Usher Syndromes - genetics / Usher Syndromes - physiopathology / Usher Syndromes - therapy / Vestibular system / Vestibule, Labyrinth - pathology / Vestibule, Labyrinth - physiopathology / Viruses