title: Overexpression of factor VII ameliorates bleeding diathesis of factor VIII-deficient mice with inhibitors.
abstract: BACKGROUND
  Factor VIII (FVIII) treatment for hemophilia A has difficulties in correcting bleeding diathesis in the presence of inhibitors.
  
  
  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.
authors.affiliation: Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi-ken 329-0498, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yasumoto
authors.forename: Seiji
authors.initials: S
authors.lastname: Madoiwa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kashiwakura
authors.forename: Akira
authors.initials: A
authors.lastname: Ishiwata
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Ohmori
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mizukami
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Sakata
authors.forename: Jun
authors.initials: J
authors.lastname: Mimuro
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D005167:Factor VII / Q000096:biosynthesis* / Q000235:genetics; D015942:Factor VIIa / Q000096:biosynthesis / Q000235:genetics; D015316:Genetic Therapy; D006467:Hemophilia A / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000628:therapy; D006470:Hemorrhage / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015996:Survival Rate; D014162:Transfection
chemical_list: D005167:Factor VII; D015942:Factor VIIa