1. ¹Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
2. ²Graduate Institute of Microbiology, National Taiwan University, Taipei, Taiwan
3. ³Department of Neurological Surgery, Tri-Service General Hospital, and the National Defense Medical Center, Taipei, Taiwan
4. ⁴Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
5. ⁵Molecular Therapy Laboratory, Department of Orthopedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA
6. ⁶Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
7. ⁷Department of Pathology, Tri-Service General Hospital, and the National Defense Medical Center, Taipei, Taiwan
8. ⁸Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
9. ⁹Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan

Correspondence: Dr M-H Tao, Institute of Biomedical Sciences, Academia Sinica, 128 Yen-Chiu-Yuan Rd., Sec. 2, Taipie 11529, Taiwan. E-mail: bmtao@ibms.sinica.edu.tw

Received 21 April 2006; Revised 20 July 2006; Accepted 20 July 2006; Published online 24 August 2006.

Abstract

RNA interference (RNAi) was reported to block hepatitis B virus (HBV) gene expression and replication in vitro and in vivo. However, it remains a technical challenge for RNAi-based therapy to achieve long-term and complete inhibition effects in chronic HBV infection, which presumably requires more extensive and uniform transduction of the whole infected hepatocytes. To increase the in vivo transfection efficiency in liver, we used a double-stranded adeno-associated virus 8-pseudotyped vector (dsAAV2/8) to deliver shRNA. HBV transgenic mice were used as an animal model to evaluate the inhibition effects of the RNAi-based gene therapy. A single administration of dsAAV2/8 vector, carrying HBV-specific shRNA, effectively suppressed the steady level of HBV protein, mRNA and replicative DNA in liver of HBV transgenic mice, leading to up to 2–3 log₁₀ decrease in HBV load in the circulation. Significant HBV suppression sustained for at least 120 days after vector administration. The therapeutic effect of shRNA was target sequence dependent and did not involve activation of interferon. These results underscore the potential for developing RNAi-based therapy by dsAAV2/8 vector to treat HBV chronic infection, and possibly other persistent liver infections as well.