Therapeutic levels of human protein C in rats after retroviral vector-mediated hepatic gene therapy.
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.[1]References
- Therapeutic levels of human protein C in rats after retroviral vector-mediated hepatic gene therapy. Cai, S.R., Kennedy, S.C., Bowling, W.M., Flye, M.W., Ponder, K.P. J. Clin. Invest. (1998) [Pubmed]
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