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Overexpression of miR-298 improves the disease phenotype in mouse model of Spinal-bulbar muscular atrophy via direct modulation of androgen receptor Open Access

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Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of the polyglutamine tract of the androgen receptor (AR) gene. Affected individuals develop slowly progressive proximal muscle weakness, muscle atrophy and fasciculations due to a mechanism of toxic gain of function. No effective therapy is currently available for this disease. The field of gene therapy has shown significant potential to slow down or prevent the onset of different neurological diseases. Amongst the many approaches for gene therapy, micro RNAs (miRNA) are viewed as powerful disease regulators. Using bioinformatics approach we identified miR-298 as a regulator of AR gene and observed significant reduction of endogenous miR-298 in SBMA in vitro models and in vivo model. Our recent study has demonstrated that adeno-associated virus (AAV) vector-medicated delivery of miR-298 can directly regulate AR levels and reduce the mutant androgen receptor toxicity in vivo. Furthermore, immunohistochemical and biochemical analyses demonstrated that early intervention of miR-298 delivered by AAV vector prevents motor neuron degeneration in the spinal cord and ameliorates muscle tissue pathology in transgenic mice. Together, our data suggests that miR-298 has a direct effect on ameliorating SBMA phenotypes and neuronal survival in vivo and therefore, it may have potential therapeutic effects for treating SBMA patients.

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