AVV-Mediated Neurotrophin Expression in the Deafened Cochlea

University Of California, San Francisco, San Francisco CA

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Abstract

ABSTRACT Neurotrophin therapy has been proposed for human cochlear implant (CI) recipients to promote improved survival of cochlear spiral ganglion (SG) neurons and/or hair cells, and thereby support optimized CI function. Our previous studies in cats deafened prior to hearing onset have shown that long-term intracochlear delivery of brain-derived neurotrophic factor (BDNF) by osmotic pumps can be effective in maintaining improved SG survival over many months, but this approach is not practical for clinical application. The studies outlined in this proposal will evaluate the potential for direct gene delivery to elicit sustained, local expression of neurotrophic factors by cells in the deafened cochlea. We will also conduct electrophysiological studies, recording from the inferior colliculus, to evaluate potential functional effects of therapy. Adeno-associated viral (AAV) vectors have been shown in several clinical trials to be safe and effective and to support long-term gene-expression. The proposed studies will assess AAV-neurotrophin (NT) vectors for efficacy of transfection, NT expression and SG neuronal survival in the cochlea of an animal model of congenital deafness. In an initial study, animals will receive AAV-GDNF (glial-derived neurotrophic factor) and AAV-GFP (green fluorescent protein) injections at 4 weeks of age and will be studied one month later to establish optimum injection parameters and protocols for immunohistochemistry, in situ hybridization and qPCR. In another study, animals will be examined 10 weeks after AAV injection (matching our prior BDNF studies). If initial results show significant neurotrophic effects on SG survival, long-term efficacy will be assessed by combining AAV injections with prolonged electrical stimulation from a CI. Further studies will compare the efficacy of AAV-BDNF and AAV-NT-3. We hypothsize that gene therapy will provide more physiological concentrations of NTs than pumps and strongly promote SG neuron and radial nerve fiber survival. At the same time, this approach also should avoid several potentially deleterious side effects seen in our previous long-term studies with high concentrations of BDNF from osmotic pumps (e.g., angiogenesis, increased peri-implant fibrosis, and ectopic, disorganized sprouting of radial nerve fibers). This research ultimately could benefit CI recipients by developing a clinical therapy for preventing auditory nerve degeneration and thereby supporting optimized implant function. Findings will be particularly relevant to pediatric CI recipients, who must depend on electrical hearing for many decades and who are most likely to benefit from improved technologies requiring good nerve survival (e.g., highly spatially restricted current fields, current steering, virtual electrodes, higher stimulation rates). Moreover, recent studies have shown that primary loss of SG neurons in human cochleae may underlie hearing loss with aging or noise damage. Thus, if NTs delivered by AAV can be shown to promote SG survival and regrowth of radial nerve fibers, this could be an important first step toward gene therapy to halt hearing loss or even restore hearing by reconnecting radial nerve fibers to hair cells in ears with hearing loss due to loss of these connections.