title: Priming of hepatocytes enhances in vivo liver transduction with lentiviral vectors in adult mice.
abstract: Lentiviral vectors are promising tools for liver disease gene therapy, because they can achieve protracted expression of transgenes in hepatocytes. However, the question as to whether cell division is required for optimal hepatocyte transduction has still not been completely answered. Liver gene-transfer efficiency after in vivo administration of recombinant lentiviral vectors carrying a green fluorescent protein reporter gene under the control of a liver-specific promoter in mice that were either hepatectomized or treated with cholic acid or phenobarbital was compared. Phenobarbital is known as a weak inducer of hepatocyte proliferation, whereas cholic acid has no direct effect on the cell cycle. This study shows that cholic acid is able to prime hepatocytes without mitosis induction. Both phenobarbital and cholic acid significantly increased hepatocyte transduction six- to ninefold, although cholic acid did not modify the mitotic index or cell-cycle entry. However, the effect of either compound was weaker than that observed after partial hepatectomy. In no cases was there a correlation between the expression of cell-cycle marker and transduction efficiency. We conclude that priming of hepatocytes should be considered a clinically applicable strategy to enhance in vivo liver gene therapy with lentiviral vectors.
authors.affiliation: INSERM U948, Biothérapies Hépatiques, CHU Hotel Dieu, 44093 Nantes Cedex, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Pichard
authors.forename: Sébastien
authors.initials: S
authors.lastname: Boni
authors.forename: William
authors.initials: W
authors.lastname: Baron
authors.forename: Tuan Huy
authors.initials: TH
authors.lastname: Nguyen
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ferry
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D019826:Cholic Acid / Q000494:pharmacology*; D017931:DNA Primers / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006400:Hematocrit; D022781:Hepatocytes / Q000187:drug effects*; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010634:Phenobarbital / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D014161:Transduction, Genetic / Q000379:methods*
chemical_list: D017931:DNA Primers; D049452:Green Fluorescent Proteins; D019826:Cholic Acid; D010634:Phenobarbital