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

• Published in: The Journal of clinical investigation 1998-06, Vol.101 (12), p.2831-2841
• Main Authors: Cai, S R, Kennedy, S C, Bowling, W M, Flye, M W, Ponder, K P
• Format: Article
• Language: English
• Subjects: Animals; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Liver - physiology; Male; Promoter Regions, Genetic; Protein C - physiology; Rats; Rats, Inbred Lew; Retroviridae
• ISSN: 0021-9738
• DOI: 10.1172/JCI1880

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.