RETROVIRUS-MEDIATED IN-VIVO GENE-TRANSFER IN THE REPLICATING LIVER USING RECOMBINANT HEPATOCYTE GROWTH-FACTOR WITHOUT LIVER-INJURY OR PARTIAL-HEPATECTOMY

Retrovirus-mediated gene delivery into hepatocytes in vivo provides lo ng-term gene expression, which is of great importance for treating mos t genetic and metabolic disorders, However, clinical application has n ot been realized because of the requirement for prior 70% partial hepa tectomy or chemical (toxic) liver injury to initiate hepatocyte replic ation at the time of retroviral gene transduction, In this paper, we d escribe a novel gene delivery system that uses recombinant hepatocyte growth factor (rHGF) prior to retrovirus-mediated in vivo gene transfe r in the liver without partial hepatectomy or liver injury, A single r etroviral infusion through the portal vein following five systemic inj ections (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- a nd 12.9-fold higher than those of controls, respectively, Modest addit ional increases in BLI and RGTE (13.4% and 0.22%, respectively) were s een after five systemic injections of 500 mu g/kg rHGF, The correlatio n between BLI and RGTE was statistically confirmed regardless of treat ment, When rats received multiple retroviral infusions through a cannu lated portal vein following five portal injections of 100 mu g/kg rHGF , RGTE was dramatically increased (1.3%) and in some areas of the live r 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.