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Gene therapy of hepatic diseases: prospects for the new millennium
  1. K SHETTY,
  2. G Y WU,
  3. C H WU
  1. Department of Medicine
  2. Division of Gastroenterology-Hepatology
  3. University of Connecticut Health Center
  4. 263 Farmington Avenue
  5. Farmington, CT 06030, USA
  1. Dr Catherine Wu. email:cwu{at}

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As we stand on the cusp of the 21st century, the prospect of treating liver diseases by the manipulation of genetic material seems to be not merely a remote possibility, but a tangible reality. The rapid advances in biotechnology over the past few decades have afforded a unique understanding of the molecular mechanisms underlying various hepatic disorders. As a result, novel and exciting techniques have been developed for the genetic modification of hepatocytes. In this article, we will highlight advances in particular areas, and lend perspective as to their future prospects.

Strategies for hepatic gene therapy


This strategy involves administration of a normal gene to replace a missing or dysfunctional gene product resulting from a defective gene, as has been illustrated by studies on the hereditary disorder familial hypercholesterolaemia. In this disease, a defect in the low density lipoprotein (LDL) receptor gene results in abnormal expression of the LDL receptor and consequent failure of clearance of LDL cholesterol.1 Using an animal model of familial hypercholesterolaemia, the Watanabe heritable hyperlipidaemic (WHHL) rabbit, investigators have been able to show the successful transduction of a functional rabbit LDL gene into target hepatocytes. This resulted in a 30–40% reduction in serum cholesterol, with the recombinant LDL receptor being detectable for up to six months.2 In clinical trials, five patients homozygous for familial hypercholesterolaemia underwent ex vivo replacement of the faulty gene.3 This was achieved by segmental hepatic resection, preparation of hepatocyte cultures, and transduction of these cultures with a recombinant retrovirus encoding the gene for the human LDL receptor. The genetically modified cells were then transplanted into the liver using portal venous cannulation. Prolonged reductions in LDL cholesterol were seen in three of the five patients, and this procedure was remarkably free of any major side effects. This study served to demonstrate the feasibility of ex …

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  • *Note added in proof: A troubling development has occurred in a clinical trial of adenoviral gene therapy for ornithine transcarbamylase deficiency. The unexplained death of one of the trial patients has resulted in the indefinite suspension of the trial.

  • Abbreviations used in this review:
    adeno-associated virus
    asialoglycoprotein receptor
    bilirubin-UDP- glucuronyltransferase
    glycogen storage disease
    hepatitis C virus
    herpes simplex virus thymidine kinase
    human acid α-glucosidase
    low density lipoprotein
    ornithine transcarbamylase
    Simian virus 40