Retroviral vector-mediated hepatic gene therapy could permantly correct metabolic disorders such as ornithine transcarbamylase deficiencies such as hemophilia or thrombophilia. We have recently demonstrated that stable and therapeutic levels of expression of two plasma proteins can be achieved in rats. However, the risks of both ex vivo and in vivio delivery methods currently limit the application of gene therapy to humans. In vivo delivery systems involve portal vein injection of retroviral vector during liver regeneration. Most investigators use a 70% partial hepatectomy to induce the hepatocyte replication that is necessary for transduction with a MoMLV-based retroviral vector. The goal of these studies is to decrease or eliminate the toxicity of the in vivo retroviral vector delivery methods in rodents and pigs. Growth factors exist that induce hepatocyte replication in vitro and invivo. These growth factors will be administered to rodents via a adenoviral vector or a s purified protein. The adenoviral vector will result in short-term expression in the liver because of the immune response to adenoviral-transduced cells. In some cases, the administration of the growth factor will be combined with portal branch occlusion, which should make the liver more responsive to lower doses of the growth factors. Portal branch occlusion induces apoptosis of hepatocytes from the occluded liver, and compensatory replication of hepatocytes in the non-occluded liver. the effect of these treatments upon hepatocyte replication and liver function will be determined. Their ability to facilitate retroviral vector transduction will be assessed by injecting a retroviral vector into the portal vein during the peak period of hepatocyte replication, and determining the level of expression of the reporter gene. If experiments are successful in rodents, we will attempt to use these approaches to induce hepatocyte replication and facilitate retroviral vector transduction in pigs. The experiments proposed here might identify an acceptable procedure for delivering retroviral vectors to livers of patients with genetic disorders.