Adenovirus-mediated gene transfer of interferon alpha improves dimethylnitrosamine-induced liver cirrhosis in rat model.
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.
Suzuki
K
K
Genetics Division, National Cancer Center Research Institute, Tokyo, Japan.
Aoki
K
K
Ohnami
S
S
Yoshida
K
K
Kazui
T
T
Kato
N
N
Inoue
K
K
Kohara
M
M
Yoshida
T
T
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D004128:Dimethylnitrosamine; D005355:Fibrosis; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D007167:Immunotherapy / Q000379:methods*; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000008:administration & dosage / Q000032:analysis / Q000235:genetics*; D008099:Liver / Q000276:immunology / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014161:Transduction, Genetic / Q000379:methods
D007371:Interferon-gamma; D004128:Dimethylnitrosamine