Factors Influencing Retroviral-Mediated Gene Transfer into HepatocytesIn Vivo

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Abstract
Direct gene transfer into hepatocytes represents an attractive alternative to organ transplantation for the treatment of genetic liver diseases. This approach is hampered either by the difficulty to obtain, cultivate, and reimplant hepatocytes or by the poor stability of the expression of the transgene. In the present report, we show that direct in vivo infection of hepatocytes with a retroviral vector following partial hepatectomy results in a life-long expression of the transgene in adult rats and mice. We demonstrate that the kinetics of hepatocyte susceptibility to infection is closely associated with the kinetics of cell division. We also present evidence that a complete vascular exclusion of the organ allows better gene transfer as compared to simple portal infusion of the viral particles, presumably through a higher volume of retrovirus-containing medium delivered to the liver. Gene therapy represents an attractive alternative to liver transplantation for the treatment of inherited hepatic diseases. We have developed a method that allows direct in vivo retroviral-mediated gene transfer into hepatocytes. We show here that a complete vascular exclusion of the organ prior to retrovirus injection and the careful monitoring of the delay between hepatectomy and infection are required to achieve a maximal and long-term stable expression of the transgene in the liver.