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Use of RNA interference to modulate liver adenoma development in a murine model transgenic for hepatitis B virus

Gene Therapy volume 19, pages 25–33 (2012)Cite this article

Abstract

Chronic hepatitis B virus (HBV) infection is closely related to the development of severe liver complications, including hepatocellular carcinoma. In previous studies, we reported that in vivo long-term HBV suppression in transgenic mice can be achieved without apparent toxicity by short hairpin RNA sequentially delivered using adeno-associated viral (AAV) vectors of different serotypes. Our goal herein was to address the clinical utility of this delivery system and, in particular, to determine whether RNA interference (RNAi) and its ability to induce long-term HBV suppression will modulate the development of HBV-associated liver pathology. As a model system, we used a unique HBV transgenic mouse model, containing a 1.3 times over length of the HBV genome, on the ICR mouse background. These transgenic mice produce high serum HBV titers comparable with human chronic HBV patients, and, importantly, manifest characteristic HBV-associated pathology, including progressive hepatocellular injury and the development of hepatocellular adenoma. Using this system, we injected animals with AAV vectors expressing either HBV-specific or a control luciferase-specific short hairpin RNA and followed animals for a total of 18 months. We report herein that AAV-mediated RNAi therapy profoundly inhibits HBV replication and gene expression, with a significant reduction in hepatic regeneration, liver enzymes and, importantly, the appearance of liver adenomas. Indeed, the therapeutic effect of RNAi correlated with the reduction in HBV titers. Our data demonstrate that appropriately designed RNAi therapy has the potential to prevent formation of HBV-associated hepatocellular adenoma.

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Acknowledgements

We thank Dr Patrick SC Leung (University of California at Davis) for the critical readings of this manuscript, Dr An-Li Huang (Institute of Biomedical Sciences, Academia Sinica) for technical help with the electron microscopy and Dr Jim-Yih Chen (Institute of Biomedical Sciences, Academia Sinica) for statistical analysis. Dr Mi-Hua Tao was a sabbatical guest at the University of California School of Medicine at Davis in 2008–2009. This work was supported by Academia Sinica Summit Program and National Research Program for Genomic Medicine grant 98-3112-B-001-030 from the National Science Council, Taiwan.

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Authors and Affiliations

  1. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    C-C Chen, C-M Chang, C-P Sun, P-Y Wu, C-h Shih & M-H Tao

  2. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan

    C-M Chang

  3. Taiwan International Graduate Program, Academia Sinica and National Yang-Ming University, Taipei, Taiwan

    C-P Sun

  4. Department of Pathology, Tri-Service General Hospital and the National Defense Medical Center, Taipei, Taiwan

    C-P Yu

  5. Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan

    K-S Jeng

  6. Department of Life Science, Tunghai University, Taichung, Taiwan

    C-P Hu

  7. Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan

    P-J Chen

  8. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

    J-C Wu

  9. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA

    M E Gershwin

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  1. C-C Chen
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Correspondence to M-H Tao.

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Chen, CC., Chang, CM., Sun, CP. et al. Use of RNA interference to modulate liver adenoma development in a murine model transgenic for hepatitis B virus. Gene Ther 19, 25–33 (2012). https://doi.org/10.1038/gt.2011.60

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