title: Rescue of Hearing by Gene Delivery to Inner-Ear Hair Cells Using Exosome-Associated AAV.
abstract: Adeno-associated virus (AAV) is a safe and effective vector for gene therapy for retinal disorders. Gene therapy for hearing disorders is not as advanced, in part because gene delivery to sensory hair cells of the inner ear is inefficient. Although AAV transduces the inner hair cells of the mouse cochlea, outer hair cells remain refractory to transduction. Here, we demonstrate that a vector, exosome-associated AAV (exo-AAV), is a potent carrier of transgenes to all inner ear hair cells. Exo-AAV1-GFP is more efficient than conventional AAV1-GFP, both in mouse cochlear explants in vitro and with direct cochlear injection in vivo. Exo-AAV shows no toxicity in vivo, as assayed by tests of auditory and vestibular function. Finally, exo-AAV1 gene therapy partially rescues hearing in a mouse model of hereditary deafness (lipoma HMGIC fusion partner-like 5/tetraspan membrane protein of hair cell stereocilia [Lhfpl5/Tmhs-/-]). Exo-AAV is a powerful gene delivery system for hair cell research and may be useful for gene therapy for deafness.
authors.affiliation: Department of Neurobiology and Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA; Department of Neurology, Massachusetts General Hospital and NeuroDiscovery Center, Harvard Medical School, Building 149, Charlestown, Boston, MA 02129, USA.
authors.forename: Bence
authors.initials: B
authors.lastname: György
authors.affiliation: Department of Neurobiology and Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Sage
authors.affiliation: Department of Neurobiology and Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Artur A
authors.initials: AA
authors.lastname: Indzhykulian
authors.affiliation: Department of Neurobiology and Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Deborah I
authors.initials: DI
authors.lastname: Scheffer
authors.affiliation: Molecular Imaging and NanoBioTechnology, UMR-5248-CBMN CNRS-University of Bordeaux-IPB, Allée Geoffroy Saint-Hilaire, F-33600 Pessac, France.
authors.forename: Alain R
authors.initials: AR
authors.lastname: Brisson
authors.affiliation: Molecular Imaging and NanoBioTechnology, UMR-5248-CBMN CNRS-University of Bordeaux-IPB, Allée Geoffroy Saint-Hilaire, F-33600 Pessac, France.
authors.forename: Sisareuth
authors.initials: S
authors.lastname: Tan
authors.affiliation: Department of Neurobiology and Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Xudong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Neurology, Massachusetts General Hospital and NeuroDiscovery Center, Harvard Medical School, Building 149, Charlestown, Boston, MA 02129, USA.
authors.forename: Adrienn
authors.initials: A
authors.lastname: Volak
authors.affiliation: Department of Neurology, Massachusetts General Hospital and NeuroDiscovery Center, Harvard Medical School, Building 149, Charlestown, Boston, MA 02129, USA.
authors.forename: Dakai
authors.initials: D
authors.lastname: Mu
authors.affiliation: Department of Neurobiology and Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Panos I
authors.initials: PI
authors.lastname: Tamvakologos
authors.affiliation: Department of Neurobiology and Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Yaqiao
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurology, Massachusetts General Hospital and NeuroDiscovery Center, Harvard Medical School, Building 149, Charlestown, Boston, MA 02129, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Fitzpatrick
authors.affiliation: Department of Cell Biology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Ericsson
authors.affiliation: Department of Neurology, Massachusetts General Hospital and NeuroDiscovery Center, Harvard Medical School, Building 149, Charlestown, Boston, MA 02129, USA; Program in Neuroscience, Harvard Medical School, Building 149, Charlestown, Boston, MA 02129, USA.
authors.forename: Xandra O
authors.initials: XO
authors.lastname: Breakefield
authors.affiliation: Department of Neurobiology and Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. Electronic address: dcorey@hms.harvard.edu.
authors.forename: David P
authors.initials: DP
authors.lastname: Corey
authors.affiliation: Department of Neurology, Massachusetts General Hospital and NeuroDiscovery Center, Harvard Medical School, Building 149, Charlestown, Boston, MA 02129, USA. Electronic address: cmaguire@mgh.harvard.edu.
authors.forename: Casey A
authors.initials: CA
authors.lastname: Maguire
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000229:Dependovirus / Q000145:classification / Q000235:genetics*; D016057:Evoked Potentials, Auditory, Brain Stem / Q000235:genetics; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006199:Hair Cells, Auditory, Inner / Q000378:metabolism*; D006309:Hearing / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D014161:Transduction, Genetic; D019076:Transgenes
keywords: LHFPL5; TMHS; adeno-associated virus vector; balance; cochlea; exosomes; gene therapy; hair cell; hearing; inner ear