Intravenous rAAV2/9 injection for murine cochlear gene delivery

Gene therapy for genetic deafness is a promising approach by which to prevent hearing loss or to restore hearing after loss has occurred. Although a variety of direct approaches to introduce viral particles into the inner ear have been described, presumed physiological barriers have heretofore precluded investigation of systemic gene delivery to the cochlea. In this study, we sought to characterize systemic delivery of a rAAV2/9 vector as a non-invasive means of cochlear transduction. In wild-type neonatal mice (postnatal day 0-1), we show that intravenous injection of rAAV2/9 carrying an eGFP-reporter gene results in binaural transduction of inner hair cells, spiral ganglion neurons and vestibular hair cells. Transduction efficiency increases in a dose-dependent manner. Inner hair cells are transduced in an apex-to-base gradient, with transduction reaching 96% in the apical turn. Hearing acuity in treated animals is unaltered at postnatal day 30. Transduction is influenced by viral serotype and age at injection, with less efficient cochlear transduction observed with systemic delivery of rAAV2/1 and in juvenile mice with rAAV2/9. Collectively, these data validate intravenous delivery of rAAV2/9 as a novel and atraumatic technique for inner ear transgene delivery in early postnatal mice.