The journal of gene medicine · 2008
Exploring gene-deleted adenoviral vectors for delivery of short hairpin RNAs and reduction of hepatitis B virus infection in mice.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Rauschhuber Christina, Xu Hui, Salazar Felix H, Marion Patricia L, Ehrhardt Anja
Аннотация
BACKGROUND: RNA interference based therapeutic approaches hold promise for the treatment of patients chronically infected with hepatitis B virus (HBV). To conquer HBV infection, long-term suppression of target transcripts in all hepatocytes without toxic effects may be required. The present study explored gene-deleted adenoviral vectors (GD-AdV) lacking all viral coding sequences for delivery of the previously described short hairpin RNA (shRNA) HBVU6no.2, which was demonstrated to result in post-transcriptional knock-down of HBV transcripts.
METHODS: We established conditions for shRNA delivery expressed from GD-AdV in vitro and in vivo and observed up to 96% shRNA-mediated knockdown of luciferase expressed in mouse liver. To investigate in vivo efficacy of HBVU6no.2 expressed from a GD-AdV, we explored a transient and a transgenic mouse model for HBV infection.
RESULTS: We observed an up to 68% drop in serum HBV surface antigen (HBsAg) levels in the transient and the transgenic mouse model for HBV infection, respectively. Interestingly, we detected an up to 86% drop in HBsAg levels in both animal models after administration of a control GD-AdV encoding beta-galactosidase. In concordance with reduced serum HBsAg levels, we observed reduced HBV replication as demonstrated by Southern blot analysis of HBV genomes.
CONCLUSIONS: The present study demonstrates that GD-AdV can be used against HBV infection but the design of DNA sequences including shRNAs contained in the vector and virus-host interactions during superinfection needs to be carefully considered.
METHODS: We established conditions for shRNA delivery expressed from GD-AdV in vitro and in vivo and observed up to 96% shRNA-mediated knockdown of luciferase expressed in mouse liver. To investigate in vivo efficacy of HBVU6no.2 expressed from a GD-AdV, we explored a transient and a transgenic mouse model for HBV infection.
RESULTS: We observed an up to 68% drop in serum HBV surface antigen (HBsAg) levels in the transient and the transgenic mouse model for HBV infection, respectively. Interestingly, we detected an up to 86% drop in HBsAg levels in both animal models after administration of a control GD-AdV encoding beta-galactosidase. In concordance with reduced serum HBsAg levels, we observed reduced HBV replication as demonstrated by Southern blot analysis of HBV genomes.
CONCLUSIONS: The present study demonstrates that GD-AdV can be used against HBV infection but the design of DNA sequences including shRNAs contained in the vector and virus-host interactions during superinfection needs to be carefully considered.