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Therapeutic levels of functional human factor X in rats after
retroviral-mediated hepatic gene therapy
M Le, T Okuyama, SR Cai, SC Kennedy, WM Bowling, MW Flye and KP Ponder
Department of Internal Medicine, Washington University School of Medicine,
St Louis, MO, USA.
Factor X deficiency results in a rare but serious bleeding disorder that
might be treated by expressing a normal factor X gene in patients. We
generated an amphotropic retroviral vector with the human FX cDNA and
delivered it to rat hepatocytes in vivo during liver regeneration. The
human alpha1-antitrypsin promoter was chosen to direct expression because
it was the most efficient of several tested in yielding expression of
alpha1-antitrypsin protein from a retroviral vector in hepatocytes in vivo.
We achieved expression of factor X in four rats at levels sufficient to
maintain hemostasis in humans (10% to 43% of normal). The factor X was
determined to be functional by using a chromogenic substrate assay after
immunoprecipitation with human specific antibodies. Expression of factor X
remained stable for more than 10 months in two rats. It is likely that
expression will be maintained for the life of the animals, because
retroviral vectors integrate into the chromosome and hepatocytes are
long-lived. The high and stable levels of expression achieved using this
liver-specific promoter overcomes one of the two major obstacles to
successful human gene therapy for hemophilia.
Volume 89,
Issue 4,
pp. 1254-1259,
02/15/1997
Copyright © 1997 by The American Society of Hematology
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