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

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
Proc Natl Acad Sci USA. 2017-08-23; 114(36): 9695-9700
DOI: 10.1073/pnas.1708894114

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Emptoz A(1)(2)(3), Michel V(1)(2)(3), Lelli A(1)(2)(3), Akil O(4), Boutet de Monvel J(1)(2)(3), Lahlou G(1)(2)(3), Meyer A(1)(2), Dupont T(1)(2)(3), Nouaille S(1)(2)(3), Ey E(5), Franca de Barros F(6), Beraneck M(6), Dulon D(7), Hardelin JP(1)(2)(3), Lustig L(8), Avan P(9), Petit C(10)(2)(3)(11), Safieddine S(10)(2)(3).

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, NewYork, NY 10034.
(9)Laboratoire de Biophysique Sensorielle, Faculté de Médecine, Universitéd’Auvergne, Biophysique Médicale, Centre Jean Perrin, 63000 Clermont-Ferrand,France.
(10)INSERM, UMR 1120, Paris, France;
(11)Collège de France, 75005 Paris, France.

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

Conflict of interest statement: Conflict of interest statement: A patent involving A.E., C.P., and S.S. (PCT/EP2016/053613) has been deposited by the Institut Pasteur, INSERM, and CNRS.

Auteurs Bordeaux Neurocampus