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Adenovirus-mediated gene transfer of interferon α improves dimethylnitrosamine-induced liver cirrhosis in rat model

Gene Therapy volume 10, pages 765–773 (2003)Cite this article

Abstract

Several lines of evidence suggest that interferon (IFN)-α is effective in suppression of liver cirrhosis (LC) as well as hepatitis C virus (HCV) infection, which is a major cause of LC in Japan. However, IFN-α often causes systemic toxicity such as flu-like symptoms, which precludes the IFN-α dose escalation required for clinical efficacy. Since IFN-α is rapidly degraded in the blood circulation, only a small amount of subcutaneously injected IFN-α protein can reach the target organ, the liver. It is expected that on-site IFN-α production in the liver overcomes the limitation of the conventional parenteral IFN-α administration. An adenovirus vector expressing the rat IFN-α gene (AxCA-rIFN) was injected intravenously into rats with dimethylnitrosamine-induced LC. While the subcutaneous IFN-α protein injection led to a transient elevation of the cytokine both in the liver and serum, the vector-mediated IFN-α gene transduction induced a significant amount of IFN-α detected in the liver but not in the serum. The injection of AxCA-rIFN prevented the progression of the rat LC, and improved the survival rate of the treated rats. Although no significant toxicity was noted in the animals, we showed that IFN-α gene expression in the liver can be efficiently downregulated by the Cre/loxP-mediated shut-off system, in case the IFN-α overdose becomes a problem. The study suggested for the first time the advantage and feasibility of IFN-α gene therapy for LC.

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Acknowledgements

This work was supported in part by a grant-in-aid for the 2nd Term Comprehensive 10-year Strategy for Japan, and by grants-in-aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan.

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Authors and Affiliations

  1. Genetics Division, National Cancer Center Research Institute, Tokyo, Japan

    K Suzuki, S Ohnami, K Yoshida & T Yoshida

  2. Section for Studies on Host-immune Response, National Cancer Center Research Institute, Tokyo, Japan

    K Aoki

  3. First Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan

    K Suzuki & T Kazui

  4. Department of Molecular Biology, Okayama University Medical School, Institute of Cellular and Molecular Biology, Okayama, Japan

    N Kato

  5. Department of Microbiology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    K Inoue & M Kohara

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  1. K Suzuki
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Suzuki, K., Aoki, K., Ohnami, S. et al. Adenovirus-mediated gene transfer of interferon α improves dimethylnitrosamine-induced liver cirrhosis in rat model. Gene Ther 10, 765–773 (2003). https://doi.org/10.1038/sj.gt.3301949

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