582. Role of MicroRNA Deregulation in Machado-Joseph Disease

Abstract

Gene InhIbItIoninfected with a mixture of wild-type and T472C HBV, a S1-resistant HBV variant, then viral dynamics were monitored during treatment with a single or combined shRNAs. RESULTS: We identified five highly potent shRNAs that reduced serum HBV DNA levels by 900-to 8,500-fold in HBV transgenic mice. In HBV-infected human liver chimeric mice, the presence of T472C mutant compromised the therapeutic efficacy of S1 and resulted in replacement of wild-type HBV by T472C HBV. In contrast, combinatorial therapy using S1 and P28, one of five potent shRNAs, markedly reduced titers for both wild-type and T472C HBV. Interestingly, treatment with P28 alone led to the emergence of escape mutants with mutations in the P28 target region. CONCLUSIONS: The presence of viral quasispecies in HBV patients might compromise efficacy of RNAi therapy by selecting shRNA-resistant HBVs. Combinatorial RNAi therapy can minimize the escape of resistant HBV mutants.