title: Porcine model of hemophilia A.
abstract: Hemophilia A is a common X chromosome-linked genetic bleeding disorder caused by abnormalities in the coagulation factor VIII gene (F8). Hemophilia A patients suffer from a bleeding diathesis, such as life-threatening bleeding in the brain and harmful bleeding in joints and muscles. Because it could potentially be cured by gene therapy, subhuman animal models have been sought. Current mouse hemophilia A models generated by gene targeting of the F8 have difficulties to extrapolate human disease due to differences in the coagulation and immune systems between mice and humans. Here, we generated a porcine model of hemophilia A by nuclear transfer cloning from F8-targeted fibroblasts. The hemophilia A pigs showed a severe bleeding tendency upon birth, similar to human severe hemophiliacs, but in contrast to hemophilia A mice which rarely bleed under standard breed conditions. Infusion of human factor VIII was effective in stopping bleeding and reducing the bleeding frequency of a hemophilia A piglet but was blocked by the inhibitor against human factor VIII. These data suggest that the hemophilia A pig is a severe hemophilia A animal model for studying not only hemophilia A gene therapy but also the next generation recombinant coagulation factors, such as recombinant factor VIII variants with a slower clearance rate.
authors.affiliation: Research Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi-ken, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kashiwakura
authors.forename: Jun
authors.initials: J
authors.lastname: Mimuro
authors.forename: Akira
authors.initials: A
authors.lastname: Onishi
authors.forename: Masaki
authors.initials: M
authors.lastname: Iwamoto
authors.forename: Seiji
authors.initials: S
authors.lastname: Madoiwa
authors.forename: Daiichiro
authors.initials: D
authors.lastname: Fuchimoto
authors.forename: Shunichi
authors.initials: S
authors.lastname: Suzuki
authors.forename: Misae
authors.initials: M
authors.lastname: Suzuki
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Sembon
authors.forename: Akira
authors.initials: A
authors.lastname: Ishiwata
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yasumoto
authors.forename: Asuka
authors.initials: A
authors.lastname: Sakata
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Ohmori
authors.forename: Michiko
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Satoko
authors.initials: S
authors.lastname: Yazaki
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Sakata
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D004195:Disease Models, Animal; D005169:Factor VIII / Q000235:genetics* / Q000378:metabolism; D023061:Gene Order; D018390:Gene Targeting; D006467:Hemophilia A / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D010641:Phenotype; D013552:Swine
chemical_list: D005169:Factor VIII