Exploring gene-deleted adenoviral vectors for delivery of short hairpin RNAs and reduction of hepatitis B virus infection in mice

Autor: Felix H. Salazar, Hui Xu, Christina Rauschhuber, Anja Ehrhardt, Patricia L. Marion
Rok vydání: 2008
Předmět:
Zdroj: The Journal of Gene Medicine. 10:878-889
ISSN: 1521-2254
1099-498X
DOI: 10.1002/jgm.1207
Popis: 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 β-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. Copyright © 2008 John Wiley & Sons, Ltd.
Databáze: OpenAIRE
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