Targeting of genes to the liver with glycoprotein carriers

Abstract

Several techniques are available to deliver foreign genes to cells in vitro. These techniques have offered valuable insights into gene regulation and expression. Many of these methods, however, have limited in vivo potential for clinical gene therapy because they compromise cell viability or cannot be targeted to desired cell types. Strategies with high potential for use in gene therapy need to satisfy several criteria: (1) use of a stable vector for the foreign DNA, (2) efficient expression of foreign DNA in host cells, and (3) a means to target a desired cell type or organ. Hepatocytes are attractive targets for gene therapy because of their large number, rich blood supply and important role in intermediary metabolism. Hepatocytes have also been found to have specific cell surface receptors that can be utilized for targeted delivery of foreign DNA. This article discusses in vitro and in vivo methods of targeted delivery and expression of foreign genes in hepatocytes with emphasis on those techniques with potential for clinical gene therapy. Methods to enhance and prolong foreign gene expression such as the use of the lysosomotropic agent chloroquine, endosomal disruption by adenovirus and influenza virus hemagglutinin HA-2 subunit, and partial hepatectomy, which has been found to augment foreign gene expression, are covered. Finally, the use of ligand-based systems to target sense and antisense DNA in gene therapy to correct metabolic disorders and the targeted delivery of protective agents to the liver are addressed.