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.
Cai
S R
SR
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Kennedy
S C
SC
Bowling
W M
WM
Flye
M W
MW
Ponder
K P
KP
D000818:Animals; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008099:Liver / Q000502:physiology*; D008297:Male; D011401:Promoter Regions, Genetic; D011486:Protein C / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D012190:Retroviridae
D011486:Protein C