Intramuscular Injection of an Adenoviral Vector Expressing Hepatocyte Growth Factor Facilitates Hepatic Transduction with a Retroviral Vector in Mice

Retroviral vectors can result in therapeutic and stable levels of expression of proteins from the liver. However, m ost retroviral vectors transduce only dividing cells, and hepatocytes are normally quiescent. The goal of this study was to determ ine if an adenoviral vector could transiently express hepatocyte growth factor (HG F) in order to induce hepatocyte replication and facilitate retroviral vector transduction of the liver. Intram uscular injection of an adenoviral vector that expressed human HGF from the cytomegalovirus promoter (Ad.C M V.HGF) resulted in m oderate levels of H GF 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. W hen a retroviral vector expressing b -galactosidase cDNA was injected into a peripheral vein during the peak period of hepatocyte replication induced by intramuscularly adm inistered Ad.C M V.HG F, 8% of hepatocytes were transduced. W e conclude that intram uscular injection of Ad.C M V.HG F is a safe and effective way to induce transient systemic expression of HG F and hepatocyte replication, and to facilitate transduction of hepatocytes with a retroviral vector.