Journal Article

Rescue of Hearing by Gene Delivery to Inner-Ear Hair Cells Using Exosome-Associated AAV

Maguire, Casey A., Tamvakologos, Panos I., György, Bence, Mu, Dakai, Breakefield, Xandra O., Ericsson, Maria, Indzhykulian, Artur A., Tan, Sisareuth, Volak, Adrienn, Fitzpatrick, Zachary, Brisson, Alain R., Wu, Xudong, Corey, David P., Scheffer, Deborah I., Li, Yaqiao, Sage, Cyrille

2017

Overview

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. [Display omitted] Gene therapy for deafness is difficult because few vectors transduce inner ear sensory cells, and those that do, transduce only one type. In a mouse model, György and colleagues demonstrate that exosome-associated AAV vectors efficiently deliver genes to all inner ear sensory cells and rescue hearing in deaf mice.

• Publisher: Elsevier Inc,Elsevier Limited,American Society of Gene & Cell Therapy
• Subject: adeno-associated virus vector / Animals / Auditory system / balance / Cells, Cultured / Cochlea / Cytomegalovirus / Deafness / Dependovirus - classification / Dependovirus - genetics / Efficiency / Evoked Potentials, Auditory, Brain Stem - genetics / exosomes / Exosomes - metabolism / Explants / Female / Gene Expression / Gene therapy / Gene transfer / Gene Transfer Techniques / Genes, Reporter / Genetic Therapy / Genetic Vectors - administration & dosage / Genetic Vectors - genetics / Hair / hair cell / Hair cells / Hair Cells, Auditory, Inner - metabolism / hearing / Hearing - genetics / Hearing loss / Hearing protection / Inner ear / LHFPL5 / Lipoma / Male / Membrane fusion / Membrane proteins / Mice / Mice, Knockout / Original / Outer hair cells / Phenotype / Retina / Software / TMHS / Toxicity / Transduction, Genetic / Transgenes / Vectors (Biology) / Vestibular system