An advance in liver-specific gene delivery

One of the more intractable problems in gene therapy over the past decade has been the development of methods to allow the selective delivery of genes to the liver and their stable maintenance and expression therein. Hepatocytes (the principal parenchymal cell of the liver) are a much sought-after target of gene therapy because they play many unique roles in the physiology of the mammalian host (1). The liver is an important site of synthesis of many plasma proteins, including those of the complement and coagulation systems. Hepatocytes also synthesize a wide variety of enzymes involved in intermediary metabolism, and mutations affecting several of these produce clinical disorders that are attractive targets for liver-specific gene therapy (2). The liver also produces low density lipoprotein (LDL) receptors (3), and hepatic restoration of wild-type LDL receptors in hosts bearing mutant receptors ameliorates their hypercholesterolemia (4). Finally, of course, there are several important chronic viral infections of the hepatocyte (notably hepatitis B and hepatitis C) for which the liver-specific delivery of antiviral compounds (e.g., INF-α or other cytokines) might be of therapeutic value. In a recent issue of PNAS, Protzer et al. (5) report new progress in the development of liver-specific viral vectors based on the genomes of hepatitis B viruses and present data on the use of these vectors to deliver antiviral cytokines to hepatocytes.