Intramuscular injection of an adenoviral vector expressing hepatocyte growth factor facilitates hepatic transduction with a retroviral vector in mice.

Abstract

Retroviral vectors can result in therapeutic and stable levels of expression of proteins from the liver. However, most retroviral vectors transduce only dividing cells, and hepatocytes are normally quiescent. The goal of this study was to determine if an adenoviral vector could transiently express hepatocyte growth factor (HGF) in order to induce hepatocyte replication and facilitate retroviral vector transduction of the liver. Intramuscular injection of an adenoviral vector that expressed human HGF from the cytomegalovirus promoter (Ad.CMV.HGF) resulted in moderate levels of HGF in blood and liver, and replication of 3 to 12% of hepatocytes. No cytopathic effect was observed in the liver, and a control adenoviral vector induced no or lower levels of replication. When a retroviral vector expressing beta-galactosidase cDNA was injected into a peripheral vein during the peak period of hepatocyte replication induced by intramuscularly administered Ad.CMV.HGF, 8% of hepatocytes were transduced. We conclude that intramuscular injection of Ad.CMV.HGF is a safe and effective way to induce transient systemic expression of HGF and hepatocyte replication, and to facilitate transduction of hepatocytes with a retroviral vector.