RRC ID |
2035
|
著者 |
Suzuki K, Aoki K, Ohnami S, Yoshida K, Kazui T, Kato N, Inoue K, Kohara M, Yoshida T.
|
タイトル |
Adenovirus-mediated gene transfer of interferon alpha improves dimethylnitrosamine-induced liver cirrhosis in rat model.
|
ジャーナル |
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.
|
巻・号 |
10(9)
|
ページ |
765-73
|
公開日 |
2003-5-1
|
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 |
4.128
|
引用数 |
32
|
WOS 分野
|
MEDICINE, RESEARCH & EXPERIMENTAL
BIOTECHNOLOGY & APPLIED MICROBIOLOGY
GENETICS & HEREDITY
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
リソース情報 |
遺伝子材料 |
AxCANCre (RDB01748) |