Retrovirus-mediated in vivo gene transfer in the replicating liver using recombinant hepatocyte growth factor without liver injury or partial hepatectomy

被引:33
|
作者
Kosai, KI
Finegold, MJ
Thi-Huynh, BT
Tewson, M
Ou, CN
Bowles, N
Woo, SLC
Schwall, RH
Darlington, GJ
机构
[1] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA
[2] Baylor Coll Med, Dept Cell Pathol, Houston, TX 77030 USA
[3] Genentech Inc, Dept Endocrine Res, S San Francisco, CA 94084 USA
关键词
D O I
10.1089/hum.1998.9.9-1293
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Retrovirus-mediated gene delivery into hepatocytes in vivo provides long-term gene expression, which is of great importance for treating most genetic and metabolic disorders, However, clinical application has not been realized because of the requirement for prior 70% partial hepatectomy or chemical (toxic) liver injury to initiate hepatocyte replication at the time of retroviral gene transduction, In this paper, we describe a novel gene delivery system that uses recombinant hepatocyte growth factor (rHGF) prior to retrovirus-mediated in vivo gene transfer in the liver without partial hepatectomy or liver injury, A single retroviral infusion through the portal vein following five systemic injections (via the tail vein) of 100 mu g/kg rHGF resulted in a 10.4% 5-bromo-2'-deoxyuridine (BrdU) labeling index (BLI) and 0.14% retroviral gene transduction efficiency (RGTE) in hepatocytes, which were 6.3- and 12.9-fold higher than those of controls, respectively, Modest additional increases in BLI and RGTE (13.4% and 0.22%, respectively) were seen after five systemic injections of 500 mu g/kg rHGF, The correlation between BLI and RGTE was statistically confirmed regardless of treatment, When rats received multiple retroviral infusions through a cannulated portal vein following five portal injections of 100 mu g/kg rHGF, RGTE was dramatically increased (1.3%) and in some areas of the liver exceeded more than 10%, There was no evidence of liver injury in any animal. This approach has great potential for clinical application in terms of avoiding invasive procedures or liver injury.
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收藏
页码:1293 / 1301
页数:9
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