Overexpression of factor VII ameliorates bleeding diathesis of factor VIII-deficient mice with inhibitors

• Published in: Thrombosis research Vol. 131; no. 5; pp. 444 - 449
• Main Authors: Yasumoto, Atsushi, Madoiwa, Seiji, Kashiwakura, Yuji, Ishiwata, Akira, Ohmori, Tsukasa, Mizukami, Hiroaki, Ozawa, Keiya, Sakata, Yoichi, Mimuro, Jun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.05.2013
• Subjects: Adeno-associated virus vector; Animals; Dependovirus - genetics; Factor VII; Factor VII - biosynthesis; Factor VII - genetics; Factor VIIa - biosynthesis; Factor VIIa - genetics; Gene therapy; Genetic Therapy; Hematology, Oncology and Palliative Medicine; Hemophilia A; Hemophilia A - drug therapy; Hemophilia A - genetics; Hemophilia A - immunology; Hemophilia A - therapy; Hemorrhage - drug therapy; Hemorrhage - genetics; Hemorrhage - therapy; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Survival Rate; Transfection; PT; Factor VIII; human alpha-1 antitrypsin; hepatic control region; prothrombin time; adeno-associated virus; activated prothrombin complex concentrate; HAAT; FVII; APCC; FX; Factor IX; FXII; cytomegalovirus; FVIII; polymerase chain reaction; Factor VIII knock out; CMV; Factor XII; Adeno-associated virus vector; Hemophilia A; Factor VII; Factor X; FIX; AAV; F8KO; HCR; SV40; simian virus 40; Gene therapy; PCR
• ISSN: 0049-3848; 1879-2472
• DOI: 10.1016/j.thromres.2013.03.007

Abstract Introduction Factor VIII (FVIII) treatment for hemophilia A has difficulties in correcting bleeding diathesis in the presence of inhibitors. Materials and Methods An adeno-associated virus type 8 (AAV8) vector containing the factor VII (FVII) gene or the activated factor VII (FVIIa) gene was used to investigate the therapeutic effect of FVII or FVIIa overexpression in FVIII-deficient mice with inhibitors. Results Following repeated human FVIII injection, FVIII-deficient mice developed anti-human FVIII antibodies that cross-reacted with mouse FVIII. High transgene expression of murine FVII or murine FVIIa was achieved using the AAV8 vector and resulted in increased blood FVII activity greater than 800% of normal murine FVII levels in vector-injected FVIII-deficient mice. Thromboelastography analysis showed significant improvements in clotting time, clot formation time, α angle, and mean clot firmness in AAV8 vector-injected FVIII-deficient mice with inhibitors. Overexpression of FVIIa ameliorated the bleeding phenotype of FVIII-deficient mice with inhibitors and significantly increased the survival rate after tail clipping. In addition, overexpression of FVII increased the survival rate of FVIII-deficient mice with inhibitors after tail clipping though it was not as efficient as FVIIa overexpression. Conclusions These data suggest that FVII overexpression is an alternative strategy for the treatment of hemophilia A with inhibitors.