Mice lacking the vesicular glutamate transporter-3 (VGLUT3) are congenitally deaf due to loss of glutamate release at the inner hair cell afferent synapse. Cochlear delivery of VGLUT3 using adeno-associated virus type 1 (AAV1) leads to transgene expression in only inner hair cells (IHCs), despite broader viral uptake. Within 2 weeks of AAV1-VGLUT3 delivery, auditory brainstem response (ABR) thresholds normalize, along with partial rescue of the startle response. Lastly, we demonstrate partial reversal of the morphologic changes seen within the afferent IHC ribbon synapse. These findings represent a successful restoration of hearing by gene replacement in mice, which is a significant advance toward gene therapy of human deafness.
Highlights
► AAV-mediated delivery of VGLUT3 results in isolated inner hair cell expression ► Within 2 weeks after AAV1-VGLUT3 delivery, ABR and CAP thresholds normalize ► Bilateral rescue with AAV1-VGLUT3 results in more robust hearing recovery ► Rescue reverses many of the pathologic changes seen at the IHC ribbon synapse
