Abstract
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.
Highlights
Hearing loss is the most common sensory impairment in humans
To investigate the inner ear transduction profile following intravenous injection of rAAV2/9-CMV-eGFP in neonatal mice, and whether transduction efficiency could be improved in a dose-dependent manner, intravascular injections were performed via the superficial temporal vein delivering a total volume of 50 μl to neonatal mice (Fig. 1b)
We show that if rAAV2/9 is used, widespread binaural transduction can be mediated in the cochlea inner hair cell (IHC), spiral ganglion neurons and vestibular hair cells
Summary
Hearing loss is the most common sensory impairment in humans. It impacts 1 of every 1000 newborns and in 70% of these babies has an underlying genetic etiology[1]. Current clinical treatment options for hereditary hearing loss are limited to sound amplification and cochlear implantation[2]. These interventions are nearly always beneficial, when compared to biological hearing performance outcomes are modest. Systemic gene transfer targeting the sensory and non-sensory epithelium in the inner ear has not been attempted (Fig. 1a). Reasons for this omission include potential systemic toxicities and two physiological barriers: the blood-brain barrier (BBB) and blood-labyrinth barrier (BLB), which obscure attempts to deliver larger molecules from the circulation into the target cells. Correspondence and requests for materials should be addressed to www.nature.com/scientificreports/
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