Gene Transfer for Auditory and Vestibular Application

The main goal of gene therapy is to transfer a foreign gene into a cell or a tissue, where the gene product is necessary for therapy or prevention. In the inner ear, both auditory and vestibular organs are important targets for gene therapy, for hereditary as well as environmental disease. The delivery vectors that shuttle transgenes into cells are rapidly improving. At present, nonviral vectors have a low efficiency of gene transfer, but they are nonpathogenic and nonimmunogenic and therefore have a practical potential for future use. In contrast, viral vectors are very efficient vehicles for gene transfer, but their use involves risks of cytotoxicity and immune response. Among the most common viral vectors are adenovirus, herpes simplex virus, adeno-associated virus, and lentivirus. We have inoculated adenoviral vectors into mature guinea pig inner ears and demonstrated robust reporter gene expression in fibroblasts and other cells of connective tissue origin, whereas hair cells and supporting cells in the auditory and vestibular epithelia were not transduced. In contrast, in young mouse inner ears, both hair cells and supporting cells can be transduced, in addition to the mesenchymal derivatives. We tested the ability of a viral vector expressing the GDNF transgene (Ad.GDNF) to protect and rescue inner ear structure and function in guinea pigs. In protection experiments, the vector was inoculated prior to an experimental lesion (acoustic or ototoxic trauma). Hearing and hair cells were protected in animals inoculated with Ad.GDNF. The vector also could rescue the organ of Corti when inoculated after an ototoxic insult. Moreover, the survival of denervated spiral ganglion neurons could be enhanced by Ad.GDNF. These experiments demonstrate the potential clinical applicability for gene therapy in the protection and rescue of inner ear structure and function.