Hereditary hearing impairment affects between 0.05 to 0.1% of the total US population. However, the precise cause of inherited auditory impairment at the molecular level is poorly understood due to the genetic heterogeneity of deafness. A strategy that overcomes the problem with genetic heterogeneity involves carrying out linkage analysis on families with nonsyndromic hereditary deafness. A three generation family with Schiebe or cochleosaccular degeneration, the most common cause of profound, congenital hearing impairment accounting for approximately 70% of cases of hereditary deafness, that is suitable for linkage studies has been identified. The immediate goal of the proposed research project is to map the location of gene responsible for Scheibe degeneration in this family using commercially available genomic markers. Once linkage to a region of the human genome is established, suitable candidate genes that reside in the linked region will be identified. These candidate genes will then be searched for the pathological mutation. The genetic study of this family and the subsequent identification of the gene which, when mutated, results in Scheibe degeneration should greatly aid in the understanding of the development and homeostatic mechanisms of the inner ear. The purpose of the second component of this proposal is to assess the utility of adeno-associated virus (AAV, a non-pathogenic human parvovirus) in introducing genetic material into the neuroepithelia of the inner ear. While gene transfer has been successfully performed in a large variety of post-mitotic cells such as myotubes, hepatocytes, endothelial cells, airway epithelial cells, and a variety of neuronal cells, the inner ear has not been studied as a target for gene therapy. The AAV containing the bacterial beta-galactosidase (beta-gal) sequence, a marker gene whose product is readily detectable, will be infused selectively into the cochlea with the aid of an osmotic minipump. The infused cochleas will be studied at various interval-transduction to assess the specificity and stability of AAV infection. Experimentally, the ability to introduce genes into the inner ear will aid in the understanding the function of cochlear proteins and control of inner ear specific genes. Therapeutically, the prompt delivery of neurotrophic factors could reduce the tissue damage and preserve hearing following injury. Positional cloning studies in several large families with hereditary, non-syndromic hearing impairment represent potential candidate genes for gene therapy. These studies will aid in designing therapeutic strategies to alleviate auditory dysfunction as well as contributing towards molecular genetic analysis of hearing.
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