Portal branch ligation induces efficient retrovirus-mediated gene delivery in rat liver

✍ Scribed by Isabelle Lorand; Corinne Vons; Tuan Nguyen; Virginie Di Rico; Aurore Coulomb; Dominique Franco; Frédérique Capron; Anne Weber

• Publisher: John Wiley and Sons
• Year: 2004
• Tongue: English
• Weight: 425 KB
• Volume: 6
• Category: Article
• ISSN: 1099-498X
• DOI: 10.1002/jgm.532

✦ Synopsis

Abstract

Background

The in vivo transduction of hepatocytes with conventional retrovirus vectors requires the induction of cell division and this can currently only be achieved by invasive surgery or by inducing severe liver damage. We hypothesised that partial portal branch ligation (PBL) could induce hepatocyte proliferation and efficient gene transfer in the rat.

Methods

We ligated the portal branch serving 70% of the liver and measured the kinetics of liver mass restoration and cell proliferation and the distribution of dividing hepatocytes after administration of 5‐bromo‐2′‐deoxyuridine. The efficiency of retrovirus‐mediated gene transfer after PBL was tested by use of β‐galactosidase‐expressing recombinant retroviruses. The viruses were administered in a single injection via the portal vein at different times after PBL and the livers of transduced animals were analysed 4 days later.

Results

We found that the number of cycling hepatocytes remained stable between 24 and 44 h after PBL (∼12.5%). Although there was a high level of inter‐animal variability, hepatocyte proliferation was always initiated in the same lobe of the liver. In animals that had undergone PBL, 19% of hepatocytes were transduced 28 h after the administration of a single high‐titre injection of retroviruses, mainly around the portal spaces.

Conclusions

PBL can mediate the efficient transduction of hepatocytes in vivo after a single intravenous injection of recombinant retroviruses. This approach is feasible in humans. Copyright © 2004 John Wiley & Sons, Ltd.