Delivery of AAV vectors to the superior olivary complex enables efficient adult cochlear transduction via axonal transport.

Significant breakthroughs have been made in translation of adeno-associated virus (AAV) vectors for hearing disorders targeting auditory hair cells (HCs). In addition to HCs, spiral ganglion neurons (SGNs) are also impacted in a large number of sensorineural hearing loss cases in adults. However when administered directly into the cochlea in rodents aged older than P1-P3, AAV-mediated SGN transduction efficiency decreases dramatically. An efficient gene-delivery method to transduce adult SGNs is needed. Our group has a track record of utilizing axonal transport to transduce brain structures distal from the site of AAV injection. We investigated whether SGNs could be transduced in adult rats following intraparenchymal AAV administration to the olivary complex. Cochlear transduction was observed with the following common AAV serotypes expressing green fluorescent protein: AAV6, AAV9, AAV-Anc80, and AAV-PhP.B. Cochlear transduction was observed with all serotypes, but the cellular tropism and efficiency of gene transfer varied across the cochlear spiral (apex, middle, base) with different AAV serotypes, with some transducing both SGNs and HCs, while others transduced SGNs or HCs exclusively. This study provides proof of concept that AAV delivery to the olivary complex can efficiently deliver transgenes to SGNs in the adult mammalian cochlea.