Expression of Human α1-Antitrypsin in Dogs After Autologous Transplantation of Retroviral Transduced Hepatocytes

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 indefini...

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Published in:	Proceedings of the National Academy of Sciences - PNAS 1992-01, Vol.89 (1), p.89-93
Main Authors:	Kay, Mark A., Baley, Patricia, Rothenberg, Steven, Leland, Frances, Fleming, Larry, Ponder, Katherine Parker, Liu, Ta-Jen, Finegold, Milton, Darlington, Gretchen, Pokorny, William, Savio L. C. Woo
Format:	Article
Language:	eng
Subjects:	Biological and medical sciences Biotechnology Canines Cell lines Cells Cultured cells Fundamental and applied biological sciences. Psychology Gene therapy Health. Pharmaceutical industry Hepatocytes Industrial applications and implications. Economical aspects Infections Liver Polymerase chain reaction Retroviral vectors Transplantation
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Summary:	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 109hepatocytes 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 α1-antitrypsin cDNA under transcriptional control of the cytomegalovirus promoter. Both animals had significant human α1-antitrypsin in the serum for 1 month. Although the serum levels of human α1-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
ISSN:	0027-8424 1091-6490