PERSISTENT EXPRESSION OF GENES TRANSFERRED IN THE FETAL-RAT LIVER VIARETROVIRUSES

The transfer of genes into the fetal liver is a promising approach for correction of inborn errors in metabolism identified in prenatal life . In this study, we demonstrate that gene transfer to the fetal rat li ver resulted in the stable expression of the gene in the hepatocytes o f the adult animals. This was achieved by a combination of gene transf er via ecotropic retroviruses in the fetal liver with subsequent parti al hepatectomy of the offspring Replication incompetent, ecotropic and amphotropic retroviruses were used to transfer the bovine growth horm one gene (bGH) linked to the promoter (-450 to +/- 73) for the P-enolp yruvate carboxykinase (PEPCK) gene into the fetal liver in the last tr imester of gestation. Amphotropic retroviruses were unable to infect t he fetal liver due to the lack of expression of their receptors. The f etal liver was infected by the ecotropic retroviruses and partial hepa tectomy of the offspring at one month of age stimulated expression of the PEPCK/bGH gene in the liver over ten fold. Expression of the gene persisted for as long as one year. A heterogeneous pattern of expressi on of the chimeric gene throughout the liver parenchymal cells was ide ntified with higher expression in the pericentral region of the liver. This zonation of expression was not expected, since the endogenous PE PCK gene is expressed in periportal hepatocytes. We suggest that, foll owing partial hepatectomy DNA replication activates expression of the proviral PEPCK/bCH gene, mainly in midzonal and pericentral hepatocyte s. Proviral sequences may influence the expression of the PEPCK/bGH ge ne in parenchymal cells in which the PEPCK promoter is not normally ac tive.