RRC ID 2035
Author Suzuki K, Aoki K, Ohnami S, Yoshida K, Kazui T, Kato N, Inoue K, Kohara M, Yoshida T.
Title Adenovirus-mediated gene transfer of interferon alpha improves dimethylnitrosamine-induced liver cirrhosis in rat model.
Journal Gene Ther.
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.
Volume 10(9)
Pages 765-73
Published 2003-5
DOI 10.1038/sj.gt.3301949
PII 3301949
PMID 12704415
MeSH 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
IF 3.203
Times Cited 28
WOS Category MEDICINE, RESEARCH & EXPERIMENTAL BIOTECHNOLOGY & APPLIED MICROBIOLOGY GENETICS & HEREDITY BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
DNA material AxCANCre (RDB01748)