Persistent Gene Expression After Retroviral Gene Transfer into Liver CellsIn Vivo

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Abstract
The development of liver-directed gene therapy protocols depends upon the ability to transfer genes into a large number of liver cells such that the genes are expressed persistently. We used a retroviral vector to transfer the gene for neomycin phosphotransferase (neo) into mouse liver cells in vivo. Direct injection of the retrovirus preparation into mitotically active (regenerating) liver parenchyma resulted in efficient gene transfer, with neo sequences detectable in the livers of every animal tested 10 weeks to 6 months later. The neo gene was expressed for at least 3 months. This methodology may eventually be applicable to the treatment of human disease. The liver provides an excellent target organ for somatic cell gene therapy due to its large size and synthetic capacity. The long-term expression, in liver cells, of genes encoding proteins such as low-density lipoprotein (LDL) receptors, clotting factors, and metabolic enzymes would provide treatments for serious illnesses for which no adequate remedies presently exist. As a prerequisite to the development of these gene therapy protocols, it is necessary to achieve reproducible gene transfer into liver cells followed by persistent expression of the transferred gene. Two methods of gene transfer in vivo, one using asialoglycoprotein-conjugated DNA and the other using retroviruses, are being developed to obtain these goals. Using a high-liter retrovirus vector to infect mouse liver cells in vivo, Kaleko et al. demonstrate reproducible gene transfer and persistent gene expression.