Adenovirus-mediated gene transfer of interferon |[alpha]| improves dimethylnitrosamine-induced liver cirrhosis in rat model

doi:doi:10.1038/sj.gt.3301949

Gene Therapy (2003) 10, 765–773. doi:10.1038/sj.gt.3301949

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

K Suzuki^1,3, K Aoki², S Ohnami¹, K Yoshida¹, T Kazui³, N Kato⁴, K Inoue⁵, M Kohara⁵ and T Yoshida¹

¹Genetics Division, National Cancer Center Research Institute, Tokyo, Japan
²Section for Studies on Host-immune Response, National Cancer Center Research Institute, Tokyo, Japan
³First Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan
⁴Department of Molecular Biology, Okayama University Medical School, Institute of Cellular and Molecular Biology, Okayama, Japan
⁵Department of Microbiology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Correspondence: Dr T Yoshida, Genetics Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan

Received 15 May 2002; Accepted 25 October 2002.

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Abstract

Several lines of evidence suggest that interferon (IFN)- alpha 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- alpha often causes systemic toxicity such as flu-like symptoms, which precludes the IFN- alpha dose escalation required for clinical efficacy. Since IFN- alpha is rapidly degraded in the blood circulation, only a small amount of subcutaneously injected IFN- alpha protein can reach the target organ, the liver. It is expected that on-site IFN- alpha production in the liver overcomes the limitation of the conventional parenteral IFN- alpha administration. An adenovirus vector expressing the rat IFN- alpha gene (AxCA-rIFN) was injected intravenously into rats with dimethylnitrosamine-induced LC. While the subcutaneous IFN- alpha protein injection led to a transient elevation of the cytokine both in the liver and serum, the vector-mediated IFN- alpha gene transduction induced a significant amount of IFN- alpha 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- alpha gene expression in the liver can be efficiently downregulated by the Cre/loxP-mediated shut-off system, in case the IFN- alpha overdose becomes a problem. The study suggested for the first time the advantage and feasibility of IFN- alpha gene therapy for LC.