title: Successful treatment of canine hemophilia by continuous expression of canine FVIIa.
abstract: Continuous expression of activated factor VII (FVIIa) via gene transfer is a potential therapeutic approach for hemophilia patients with or without inhibitory antibodies to human factor VIII (FVIII) or IX (FIX). Here, we investigate whether gene transfer of an engineered canine FVIIa (cFVIIa) transgene can affect hemostasis in a canine model of hemophilia, a good predictor of efficacy of hemophilia treatments. Purified recombinant cFVIIa exhibited 12-fold higher tissue factor-dependent activity than purified recombinant zymogen cFVII. Subsequently, we generated a serotype 8 recombinant adeno-associated viral vector expressing cFVIIa from a liver-specific promoter. Vector delivery via the portal vein in hemophilia A and B dogs was well tolerated, and long-term expression of cFVIIa resulted in a shortening of the prothrombin time, partial correction of the whole blood clotting time and thromboelastography parameters, and a complete absence of spontaneous bleeding episodes. No evidence of hepatotoxicity, thrombotic complications, or inhibitory immune response was found. These data provide the first evidence for in vivo efficacy and safety of continuously expressed FVIIa as a FVIII/FIX-bypassing agent in a large animal model of hemophilia, avoiding the risk of inhibitor formation associated with bolus FVIII or FIX infusion.
authors.affiliation: Division of Hematology, Children's Hospital of Philadelphia, PA 19104, USA.
authors.forename: Paris
authors.initials: P
authors.lastname: Margaritis
authors.forename: Elise
authors.initials: E
authors.lastname: Roy
authors.forename: Majed N
authors.initials: MN
authors.lastname: Aljamali
authors.forename: Harre D
authors.initials: HD
authors.lastname: Downey
authors.forename: Urs
authors.initials: U
authors.lastname: Giger
authors.forename: Shangzhen
authors.initials: S
authors.lastname: Zhou
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Merricks
authors.forename: Aaron
authors.initials: A
authors.lastname: Dillow
authors.forename: Mirella
authors.initials: M
authors.lastname: Ezban
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Nichols
authors.forename: Katherine A
authors.initials: KA
authors.lastname: High
mesh_terms: D000818:Animals; D019774:Blood Coagulation Factor Inhibitors / Q000235:genetics / Q000378:metabolism; D000229:Dependovirus; D004195:Disease Models, Animal; D004285:Dogs; D015942:Factor VIIa; D015870:Gene Expression; D015316:Genetic Therapy; D006467:Hemophilia A / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D006470:Hemorrhage / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D006801:Humans; D008099:Liver / Q000378:metabolism; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D011517:Prothrombin Time; D013916:Thrombelastography
chemical_list: D019774:Blood Coagulation Factor Inhibitors; D015942:Factor VIIa