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Human Factor IX Corrects the Bleeding Diathesis of Mice With Hemophilia
B
Szu-Hao Kung,
J. Nathan Hagstrom,
Darrell Cass,
Shing Jen Tai,
Hui-Feng Lin,
Darrel W. Stafford, and
Katherine A. High
From the Departments of Pediatrics and Pathology, and the Department
of Surgery, University of Pennsylvania and the Children's Hospital of
Philadelphia, Philadelphia, PA; and the Department of Biology, the
University of North Carolina at Chapel Hill.
Mice with hemophilia B have been engineered using gene targeting
techniques. These animals exhibit severe factor IX deficiency and a
clinical phenotype that mirrors the human disease. We have bred the
founder animals onto two different strains of mice, C57B1/6 and CD-1,
and have sought to determine whether adenoviral vectors expressing
human factor IX could correct the bleeding diathesis of mice with
hemophilia B. Initial experiments showed that purified plasma-derived
human factor IX added to murine factor IX-deficient plasma resulted in
complete correction of the activated partial thromboplastin time
(aPTT), and that injection of 1011 particles
of an adenoviral vector expressing human factor IX resulted in
normalization of a modified aPTT in mouse plasma. As an additional
method of assessing the function of human factor IX in the murine
coagulation system, bleeding times were performed in normal,
hemophilic, and adenoviral-treated hemophilic mice. By two different
bleeding-time techniques, the treated hemophilic mice gave values
identical to normal littermate controls, whereas the untreated
hemophilic mice exhibited heavy blood loss and prolonged bleeding.
There was a marked difference in antibody formation in the two strains
of mice; 100% of the hemophilic CD-1 mice formed antibodies to human
factor IX, but none of the C57B1/6 mice did. These data suggest that
the C57B1/6 hemophilic mice will be more useful for gene transfer
studies, while the CD-1 hemophilic mice may be of greater utility in
studying the development of inhibitors.
Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 784-790
© 1998 by The American Society of Hematology.
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