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Research Article Free access | 10.1172/JCI1880

Therapeutic levels of human protein C in rats after retroviral vector-mediated hepatic gene therapy.

S R Cai, S C Kennedy, W M Bowling, M W Flye, and K P Ponder

Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Find articles by Cai, S. in: JCI | PubMed | Google Scholar

Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Find articles by Kennedy, S. in: JCI | PubMed | Google Scholar

Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Find articles by Bowling, W. in: JCI | PubMed | Google Scholar

Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Find articles by Flye, M. in: JCI | PubMed | Google Scholar

Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Find articles by Ponder, K. in: JCI | PubMed | Google Scholar

Published June 15, 1998 - More info

Published in Volume 101, Issue 12 on June 15, 1998
J Clin Invest. 1998;101(12):2831–2841. https://doi.org/10.1172/JCI1880.
© 1998 The American Society for Clinical Investigation
Published June 15, 1998 - Version history
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Abstract

Protein C deficiency results in a thrombotic disorder that might be treated by expressing a normal human protein C (hPC) gene in patients. An amphotropic retroviral vector with a liver-specific promoter and the hPC cDNA was delivered to rat hepatocytes in vivo during liver regeneration. Expression of hPC varied from 55 to 203 ng/ml (1.3-5.0% of normal) for 2 wk after transduction. Expression increased to an average of 900 ng/ml (22% of normal) in some rats and was maintained at stable levels for 1 yr. All of these rats developed anti-hPC antibodies and exhibited a prolonged hPC half-life in vivo. The hPC was functional as determined by a chromogenic substrate assay after immunoprecipitation. We conclude that most rats achieved hPC levels that would prevent purpura fulminans, and that hepatic gene therapy might become a viable treatment for patients with severe homozygous hPC deficiency. Anti-hPC antibodies increased the hPC half-life and plasma levels in some rats, but did not interfere with its functional activity. Thus, the development of antibodies against a plasma protein does not necessarily abrogate its biological effect in gene therapy experiments.

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