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, Nobuyuki Kato, K. Inoue, M. Kohara, T. Yoshida

Research output: Contribution to journalArticle

32 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 2003

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Dimethylnitrosamine
Adenoviridae
Liver Cirrhosis
Interferons
Genes
Liver
Injections
Blood Circulation
Virus Diseases
Serum
Hepacivirus
Genetic Therapy

Keywords

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

ASJC Scopus subject areas

  • Genetics

Cite this

Adenovirus-mediated gene transfer of interferon α improves dimethylnitrosamine-induced liver cirrhosis in rat model. / Suzuki, K.; Aoki, K.; Ohnami, S.; Yoshida, K.; Kazui, T.; Kato, Nobuyuki; Inoue, K.; Kohara, M.; Yoshida, T.

In: Gene Therapy, Vol. 10, No. 9, 05.2003, p. 765-773.

Research output: Contribution to journalArticle

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, vol. 10, no. 9, pp. 765-773. https://doi.org/10.1038/sj.gt.3301949
Suzuki, K. ; Aoki, K. ; Ohnami, S. ; Yoshida, K. ; Kazui, T. ; Kato, Nobuyuki ; Inoue, K. ; Kohara, M. ; Yoshida, T. / Adenovirus-mediated gene transfer of interferon α improves dimethylnitrosamine-induced liver cirrhosis in rat model. In: Gene Therapy. 2003 ; Vol. 10, No. 9. pp. 765-773.
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