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Sensorineural hearing loss (SNHL) affects millions of people. Genetic mutations play a large and direct role in both congenital and late-onset cases of SNHL (e.g., age-dependent hearing loss, ADHL). Although hearing aids can help moderate to severe hearing loss the only effective treatment for deaf patients is the cochlear implant (CI). Gene- and cell-based therapies potentially may preserve or restore hearing with more natural sound perception, since their theoretical frequency resolution power is much higher than that of cochlear implants. These biologically-based interventions also carry the potential to re-establish hearing without the need for implanting any prosthetic device; the convenience and lower financial burden afforded by such biologically-based interventions could potentially benefit far more SNHL patients. Recently major progress has been achieved in preclinical studies of cochlear gene therapy. This review critically evaluates recent advances in the preclinical trials of gene therapies for SNHL and the major remaining challenges for the development and eventual clinical translation of this novel therapy. The cochlea bears many similarities to the eye for translational studies of gene therapies. Experience gained in ocular gene therapy trials, many of which have advanced to clinical phase III, may provide valuable guidance in improving the chance of success for cochlear gene therapy in human trials. A discussion on potential implications of translational knowledge gleaned from large numbers of advanced clinical trials of ocular gene therapy is therefore included.

Background: Planar cell polarity (PCP) signaling regulates the coordinated polarization of cells and is required for the normal development and function of many tissues. Previous studies have identified conserved PCP genes, such as Van Gogh-like 2 (Vangl2) and Prickle (Pk), in the regulation of coordinated orientation of inner ear hair cells and female reproductive tract development. Testin shares a PET-LIM homology with Pk. It is not clear whether Testin acts in PCP processes in mammals. Results: We identified Testin as a Vangl2-interacting protein through a 2-hybrid screen with a cochlea cDNA library. Testin is enriched to cell–cell boundaries in the presence of Vangl2 in cultured cells. Genetic inactivation of Testin leads to abnormal hair cell orientation in the vestibule and cellular patterning defects in the cochlea. In addition, Testin genetically interacts with Vangl2 to regulate hair cell orientation in the cochlea and the opening of the vaginal tract. Conclusions: Our findings suggested Testin as a gene involved in coordinated hair cell orientation in the inner ear and in female reproductive tract development. Furthermore, its genetic interaction with Vangl2 implicated it as a potential molecular link, responsible for mediating the role of Vangl2-containing membranous PCP complexes in directing morphologic polarization. Developmental Dynamics 242:1454–1465, 2013. © 2013 Wiley Periodicals, Inc.