Forbes, SJ and Themis, M and Alison, MR and Selden, C and Coutelle, C and Hodgson, HJF (1998) Retroviral gene transfer to the liver in vivo during tri-iodothyronine induced hyperplasia. GENE THER , 5 (4) 552 - 555.
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The liver is an important target organ for gene therapy but its mitotic quiescence makes it resistant to integrative gene transfer. Retrovirus-based vectors integrate into liver cells in vivo but require the liver to be primed before transduction; experimentally a 70% hepatectomy is commonly used to stimulate regeneration, rendering the liver susceptible to transduction during the resulting wave of cell proliferation. Our aim was to develop a clinically acceptable method of inducing hepatocyte replication before in vivo retroviral gene transfer which is both simple and effective. We have used the physiological hormone tri-iodothyronine (T3) to stimulate hepatocyte replication. A single dose of T3 (400 mu g/100 g bw) was given subcutaneously to euthyroid rats. This produced a labelling index of 31.7% in the hepatocyte population without histological or biochemical evidence of preceding liver damage. Following T3 administration the rat livers were transfected in vivo with an amphotropic retrovirus, TELCeB/AF-7 which encodes the beta-galactosidase reporter gene together with a nuclear localisation signal. Transgene expression was noted only within the liver where 1.3% of hepatocytes expressed the beta-galactosidase enzyme. This compared to 5.2% of hepatocytes transduced following a 70% hepatectomy, and 0.02% in animals receiving neither T3 nor partial hepatic resection before transduction. T3 administration is a simple way to prime the liver before in vivo retroviral vector-based gene transfer.
|Title:||Retroviral gene transfer to the liver in vivo during tri-iodothyronine induced hyperplasia|
|Keywords:||gene therapy, liver, tri-iodothyronine, retrovirus, IN-VIVO, THERAPY, TRANSDUCTION, CELLS, PROLIFERATION, REGENERATION, EXPRESSION, INVIVO|
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