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

K. Suzuki, K. Aoki, S. Ohnami, K. Yoshida, T. Kazui, N. Kato, K. Inoue, M. Kohara, T. Yoshida

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33 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)765-773
Number of pages9
JournalGene Therapy
Volume10
Issue number9
DOIs
Publication statusPublished - May 1 2003

Keywords

  • Adenovirus
  • Gene transfer
  • Hepatitis C virus
  • Interferon
  • Liver cirrhosis

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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  • Cite this

    Suzuki, K., Aoki, K., Ohnami, S., Yoshida, K., Kazui, T., Kato, N., Inoue, K., Kohara, M., & Yoshida, T. (2003). Adenovirus-mediated gene transfer of interferon α improves dimethylnitrosamine-induced liver cirrhosis in rat model. Gene Therapy, 10(9), 765-773. https://doi.org/10.1038/sj.gt.3301949