Cochlear gene therapy targeting the protection against aging related hearing loss and neuronal degeneration

Age-related hearing loss (AHL), or presbycusis, impacts more than 40% of people over 65 by decreasing their communication ability as well as increasing the risk of dementia. AHL is accelerated by noise exposure. There is no medical treatment right now or in the near future to cure AHL after it is established. However, it is possible to slow down the development of AHL, and protect the inner ear from other toxic factors such as noise. Gene therapy tries to alter the function of genes or introduce new ones in order to treat or prevent disease. The inner ear is an ideal organ for gene therapy because it is isolated from other organs, so that any genetic manipulation won't produce side effects in other organs. Using a mouse model, we have shown that over-production a protein called X-linked inhibitor of apoptosis protein (XIAP) by gene over-expression can significantly delay AHL and prevent inner ear damage by noise and ototoxic drugs. We also have developed an efficient and minimally invasive method for inner ear gene transfection through the round window membrane, which is the easiest access route to the inner ear in humans. In the proposed the study, we will continue to see how much local XIAP gene insertion will protect animals from AHL. This experiment takes a long time as we have to wait for aging. We will extend our cochlear protection by transfection of neurotrophin-3 (NT-3), which is a protein that can protect neurons and promote the repair of nerve fibers and synapses. The combination of XIAP and NT-3 is likely to provide better protection against AHL and noise induced damage than either alone. We will further optimize our round window approach of gene transfection so that it can be used in humans. In addition, we will perform gene transfection through implanted electrode of the cochlear implants, devices used to restore hearing by electrical stimulation, in the hope that this will reduce cell death due to electrode insertion and long term nerve loss.