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

Gene Ther. 2003 May;10(9):765-73. doi: 10.1038/sj.gt.3301949.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • Dimethylnitrosamine
  • Fibrosis
  • Genetic Therapy / methods*
  • Genetic Vectors / administration & dosage*
  • Immunotherapy / methods*
  • Injections, Subcutaneous
  • Interferon-gamma / administration & dosage
  • Interferon-gamma / analysis
  • Interferon-gamma / genetics*
  • Liver / immunology
  • Liver / pathology
  • Liver Cirrhosis, Experimental / immunology
  • Liver Cirrhosis, Experimental / pathology
  • Liver Cirrhosis, Experimental / therapy*
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Transduction, Genetic / methods

Substances

  • Interferon-gamma
  • Dimethylnitrosamine