Expression of human alpha 1-antitrypsin in dogs after autologous transplantation of retroviral transduced hepatocytes.
- 1 January 1992
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 89 (1) , 89-93
- https://doi.org/10.1073/pnas.89.1.89
Abstract
The liver represents an excellent organ for gene therapy since many genetic disorders result from the deficiency of liver-specific gene products. We have previously demonstrated that transgenic mouse hepatocytes can be heterologously transplanted into congenic recipients where they survived indefinitely and continued to function as hepatocytes. Here we demonstrate the autologous transplantation of retrovirally transduced canine hepatocytes. At least 1 x 10(9) hepatocytes or 5% of the liver mass can be transplanted by the portal vasculature. In two animals we have transplanted hepatocytes transduced with a retroviral vector containing the human alpha 1-antitrypsin cDNA under transcriptional control of the cytomegalovirus promoter. Both animals had significant human alpha 1-antitrypsin in the serum for 1 month. Although the serum levels of human alpha 1-antitrypsin eventually fell due to inactivation of the cytomegalovirus promoter, PCR analysis demonstrated that a significant fraction of transduced hepatocytes migrated to the liver and continued to survive in vivo. The results suggest that gene therapy of hepatic deficiencies may be achieved by hepatocellular transplantation after genetic reconstitution with the use of promoters of cellular genes that are active in the normal liver.Keywords
This publication has 18 references indexed in Scilit:
- Permanent engraftment and function of hepatocytes delivered to the liver: Implications for gene therapy and Liver RepopulationHepatology, 1991
- Long-term in vivo expression of retrovirus-mediated gene transfer in mouse fibroblast implants.Proceedings of the National Academy of Sciences, 1991
- Mouse hepatocytes migrate to liver parenchyma and function indefinitely after intrasplenic transplantation.Proceedings of the National Academy of Sciences, 1991
- Temporary amelioration of hyperlipidemia in low density lipoprotein receptor-deficient rabbits transplanted with genetically modified hepatocytes.Proceedings of the National Academy of Sciences, 1990
- Applications of the Polymerase Chain Reaction in Retroviral-Mediated Gene Transfer and the Analysis of Gene-Marked Human TIL CellsHuman Gene Therapy, 1990
- Expression of human adenosine deaminase in murine hematopoietic cells.Molecular and Cellular Biology, 1988
- Correction of the genetic defect in hepatocytes from the Watanabe heritable hyperlipidemic rabbit.Proceedings of the National Academy of Sciences, 1988
- Retrovirus-mediated transduction of adult hepatocytes.Proceedings of the National Academy of Sciences, 1988
- Distribution of glutamine synthetase and carbamoyl-phosphate synthetase I in vertebrate liver.Proceedings of the National Academy of Sciences, 1988
- Expression of retrovirally transduced genes in primary cultures of adult rat hepatocytes.Proceedings of the National Academy of Sciences, 1987