The cerebellum is a region of the brain that plays a major role in the control of movement and cognition. Spinocerebellar Ataxia Type 1 (SCAT) is a fatal human disorder that is one of the least five inherited ataxias, and a total of at least eight neurodegenerative disease, each caused by the expression of a mutant protein containing an expanded polyglutamine region. Pathogenesis is due to a gain of function conferred by mutant ataxin-1 protein and has been recapitulated in a transgenic mouse model resulting in degeneration of neuronal Purkinje cells in the cerebellum. Recently, we have observed that introduction of marker Adeno-associated virus in the deep nuclei of the cerebellum results in a marked specificity for uptake and expression in Purkinje cells. Here we propose to apply this gene transfer methodology to the treatment of ataxia in the SCAI transgenic mouse system.
In Aim 1, conditions will be optimized for the use of AAV to introduce genes into Purkinje cells in the approaches (ribozymes, antisense) will be devised for down-regulating expression of ataxin-1. Finally, into the cerebellum, testing recipients for improvements histopathologically and in a series of motor and cognitive tests to assess cerebellar function. Results from this study will provide an assessment of the potential effectiveness of AAV-mediated gene transfer as an approach to the treatment of cerebellar diseases of the brain, but in particular for the purpose of treating the unique series of dominantly inherited neurological disorders recently discovered in humans which are associated with unstable trinucleotide repeats.
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