Progressive hearing loss is a common feature of many lysosomal storage diseases (LSDs). These diseases are usually caused by an inherited deficiency in the activity of one of the hydrolases that function within the lysosomes. As a result, partially degraded substrate accumulates within lysosomes, causing a progressive impairment of cellular and organ function. The hearing loss is usually mixed; the conductive component can be accounted for by ossicle malformation, incomplete pneumatization and chronic otitis media, but the mechanisms underlying the sensorineural component are unknown. Furthermore, vestibular function has been examined only in patients with Fabry disease. Since effective therapies are now being developed for many of the LSDs, it is crucial to understand the otological manifestations of this group of diseases and the impact of these therapies on the underlying middle and inner ear defects. I propose to determine the extent and immediate cause(s) of hearing and vestibular dysfunction in six mouse models of different LSDs: MPS I/Hurler, MPS II/Hunter, MPS IIIB/Sanfilippo B, MPS VII/Sly, Fabry, and Niemann- Pick A/B. All of the human counterparts have associated hearing loss except Niemann-Pick A/B. Since these diseases all share impaired degradation of the carbohydrate component of cell-surface and extracellular macromolecules, the findings of this study will provide insights to potentially common mechanisms underlying the hearing and vestibular dysfunction in LSDs. In addition, virus- mediated gene transfer studies already in progress in MPS VII mice will be extended to examine the effects of therapy on the middle and inner ear. These studies will lay the groundwork for designing rational treatment therapies that will preserve or improve hearing and vestibular function.
The specific aims of this application are: (1) to determine the extent and progression of hearing deficits in six mouse models of lysosomal storage diseases; (2) to determine the extent and progression of balance deficits in these mouse models; and (3) to determine the efficacy of gene therapy in correcting structural and functional deficits contributing to hearing and balance disturbances in MPS VII mice, a prototype LSD model.
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