Though cochlear implantation has profoundly influenced our treatment of children with congenital deafness, there are still significant limitations in function with an implant, and these results cannot compare to native hearing (Kral and O’Donoghue, 2010). Thus, there remains intense interest in restoring normal organ of Corti function through techniques

such as hair cell regeneration and gene therapy (Di Domenico et al., 2011). To date, a majority of the research in this arena has focused on cochlear hair cell regeneration, applicable to the most common forms of hearing loss including presbycusis, noise damage, infection, and ototoxicity. Several studies have now demonstrated regeneration of hair cells in injured mice cochlea and improvement of both hearing and balance with virally mediated delivery of Math1 ( Baker et al., Rapamycin supplier 2009, Husseman and Raphael, 2009, Izumikawa et al., 2008, Kawamoto et al., 2003, Praetorius et al., 2010 and Staecker et al., 2007). While these efforts in wild-type animals are quite important, they still do not address the problem of an underlying causative genetic mutation. In such a scenario, even successfully regenerated hair cells will still ZD1839 mouse be subject to the innate genetic mutation that led to

hair cell loss in the first place. To date, efforts to restore hearing in this type of hearing loss with gene therapy have been met with limited success ( Maeda et al., 2009), and no study has reported the reversal of deafness in an animal model of genetic deafness. Previous reports have described a mouse model of hereditary deafness, which occurs as a result of a null mutation in the gene coding for the vesicular glutamate transporter-3 (VGLUT3) (Obholzer et al., 2008, Ruel et al., 2008 and Seal et al., 2008). Synaptic transmission mediated by glutamate requires transport of the excitatory amino acid into secretory vesicles by a family of three vesicular glutamate transporters (Fremeau

old et al., 2004 and Takamori et al., 2002). We previously demonstrated that inner hair cells of the cochlea express VGLUT3 and that mice lacking this transporter are congenitally deaf (Seal et al., 2008). Hearing loss in these mice is due to the elimination of glutamate release by inner hair cells and hence to the loss of synaptic transmission at the IHC-afferent nerve synapse. Subsequent studies have shown that a missense mutation in the human gene SLC17A8, which encodes VGLUT3, might underlie the progressive high-frequency hearing loss seen in autosomal dominant DFNA25 (Ruel et al., 2008). Here we report the successful restoration of hearing in the VGLUT3 knockout (KO) mouse using virally mediated gene delivery.