Coexpression of p21WAF1/CIP1 in adenovirus vector transfected human primary hepatocytes prevents apoptosis resulting in improved transgene expression

被引:0
作者
G Wolff
A Schumacher
A K Nuessler
V Ruppert
L Karawajew
E Wehnes
P Neuhaus
B Dörken
机构
[1] Humboldt University of Berlin,Department of Hematology
[2] Max Delbrueck Center for Molecular Medicine,Department of Cell Biology
[3] Institute of Biology,Department of General
[4] Humboldt University of Berlin,undefined
[5] Visceral,undefined
[6] and Transplantation Surgery,undefined
[7] Humboldt University of Berlin,undefined
来源
Gene Therapy | 2003年 / 10卷
关键词
p21; cell cycle; apoptosis; gene therapy;
D O I
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中图分类号
学科分类号
摘要
Replication-deficient adenovirus (Ad vector) is one of the most effective gene transfer systems. However, its employment in human gene therapy trials is hampered by Ad vector associated cytotoxicity and induction of apoptosis of the infected cells. Here, we identify one underlying mechanism as uncoupling of S phase and mitosis of the cell cycle leading to apoptosis and decline of transgene expression. Moreover, we demonstrate a strategy to avoid Ad vector associated cytotoxicity and induction of apoptosis in human primary hepatocytes by coinfection of Ad vector carrying the cDNA of choice and the cell cycle regulator p21WAF1/CIP1 (p21). In addition, animal experiments were performed using Ad vector directed coexpression of p21 and human α 1-antitrypsin. As serum analysis of α 1-antitrypsin after Ad vector mediated gene transfer to the liver of mice revealed, this strategy resulted also in the improvement of transgene expression by two orders of magnitude. These data suggest that coexpression of p21 and Ad vector carrying a therapeutic gene may be a promising strategy to avoid cytotoxicity and induction of apoptosis leading to improved safety in human gene therapy.
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页码:668 / 677
页数:9
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