Abstract
The use of viral vectors for inner ear gene therapy is receiving increased attention for treatment of genetic hearing disorders. Most animal studies to date have injected viral suspensions into neonatal ears, via the round window membrane. Achieving transduction of hair cells, or sensory neurons, throughout the cochlea has proven difficult, and no studies have been able to efficiently transduce sensory cells in adult ears while maintaining normal cochlear function. Here, we show, for the first time, successful transduction of all inner hair cells and the majority of outer hair cells in an adult cochlea via virus injection into the posterior semicircular canal. We used a “designer” AAV, AAV2/Anc80L65, in which the main capsid proteins approximate the ancestral sequence state of AAV1, 2, 8, and 9. Our injections also transduced ~10% of spiral ganglion cells and a much larger fraction of their satellite cells. In the vestibular sensory epithelia, the virus transduced large numbers of hair cells and virtually all the supporting cells, along with close to half of the vestibular ganglion cells. We conclude that this viral vector and this delivery route hold great promise for gene therapy applications in both cochlear and vestibular sense organs.
Highlights
In addition to the need for vectors for cellular transduction, one of the challenges for inner ear gene therapies is achieving local delivery without damaging the delicate structures of the inner ear
The three commonly used routes for drug/virus delivery into the inner ear are 1) via the round window membrane, at the base of the cochlear spiral, where it faces the middle ear space, 2) via a hole drilled through the cochlear capsule into the cochlear fluid spaces near the round window, or 3) through a hole drilled into the posterior semicircular canal where it runs near the external surface of the skull[16,17,18,20,22,23,24,25]
Our studies show that AAV2/Anc80L65 via posterior semicircular canal injections targets virtually 100% of inner hair cell (IHC) throughout the cochlear spiral, as well as a significant fraction of outer hair cell (OHC)
Summary
In addition to the need for vectors for cellular transduction, one of the challenges for inner ear gene therapies is achieving local delivery without damaging the delicate structures of the inner ear. In our experience in animal models, injection through the semicircular canals is the least traumatic to the cochlea To date these approaches have not yielded widespread hair cell transduction in the adult ear without elevating cochlear thresholds. In a mouse model, that AAV injections into the posterior semicircular canal via an optimized procedure in the adult mouse can be made without causing any thresholds shift, suprathreshold dysfunction, or hair cell damage, even to the delicate high-frequency regions at the extreme basal tip of the cochlear spiral. Our injections appear to transduce all of the supporting cells in all the sensory epithelia of the saccule, utricle and semicircular canals This combination of technical approaches should be useful for future development of gene therapies for sensorineural hearing loss
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