Hepatocyte-based gene therapy |
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Authors: | Guha C Roy-Chowdhury N Jauregui H Roy-Chowdhury J |
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Affiliation: | (1) Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY, USA, US;(2) Marion Bessin Liver Research Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA, US;(3) Departments of Medicine and Molecular Genetics, Albert Einstein College of Medicine, New York, NY, USA, US;(4) Department of Pathology, Brown University School of Medicine, Providence, RI, USA, US;(5) Multicell Associates, Warwick, RI, USA, US |
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Abstract: | Hepatocyte-based gene therapy may be used to replace a missing gene product, confer proliferating ability to cultured hepatocytes, prevent allograft rejection, massively repopulate the host liver, or grow xenogeneic hepatocytes in mammalian liver. Gene transfer into isolated hepatocytes can be accomplished via nonviral or viral vectors, the viral vectors being more useful at this time. Common recombinant viruses that integrate into the host genome include murine leukemia retroviruses and lentiviruses, adenoassociated virus, and the T-antigen-deleted SV40 virus. Episomal viruses, such as adenoviruses, permit efficient gene transfer, but the transgene is lost upon proliferation of the transplanted hepatocyte in the host. Hybrid viruses that combine the high transduction efficiency of adenoviral vectors and the integrative capacity of other vectors, such as adenoassociated viruses, have been designed. Massive repopulation of the liver by transplanted hepatocytes can be achieved if a mitotic stimulus to the transplanted cells is combined with prevention of proliferation of the host hepatocytes. Treatment with a plant alkaloid or retrorsine, or preparative irradiation of the liver can be used to inhibit host hepatocellular proliferation, while partial hepatectomy, expression of Fas ligand, or thyroid hormone administration can be used as a mitotic stimulus to the transplanted cells. Received: July 4, 2000 / Accepted: October 13, 2000 |
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Keywords: | Hepatocyte transplantation Gene therapy Liver diseases Vectors Viral Nonviral Immortalization of hepatocytes |
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