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

The Journal of Clinical Investigation
S R CaiK P Ponder

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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Citations

Jan 20, 2000·Trends in Cardiovascular Medicine·K P Ponder
Sep 25, 1999·Human Gene Therapy·R J Kaufman
Nov 20, 2008·Biochemical and Biophysical Research Communications·Hyeon LeeMeehyein Kim
Jun 16, 2001·Molecular Therapy : the Journal of the American Society of Gene Therapy·C S SteinP B McCray
Apr 12, 2002·Molecular Therapy : the Journal of the American Society of Gene Therapy·Dominique AubertNicolas Ferry
Apr 26, 2001·Molecular Therapy : the Journal of the American Society of Gene Therapy·J E McCormackJ Greengard
Sep 14, 2000·Molecular Therapy : the Journal of the American Society of Gene Therapy·C GaoK P Ponder

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