title: Novel therapeutic approach for hemophilia using gene delivery of an engineered secreted activated Factor VII.
abstract: Hemophilia is a bleeding disorder caused by mutations in the genes encoding coagulation Factor VIII (FVIII) or FIX. Current treatment is through intravenous infusion of the missing protein. The major complication of treatment is the development of neutralizing Ab's to the clotting factor. Infusion of recombinant activated human Factor VII (rhFVIIa), driving procoagulant reactions independently of human FVIII (hFVIII) or hFIX, has been successful in such patients and could in theory provide hemostasis in all hemophilia patients. However, its high cost and short half-life have limited its use. Here, we report a novel treatment strategy with a recombinant adeno-associated virus vector delivering a modified FVII transgene that can be intracellularly processed and secreted as activated FVII (FVIIa). We show long-term expression, as well as phenotypic correction of hemophilia B mice following gene transfer of the murine FVIIa homolog, with no evidence of thrombotic complications at these doses. These data hold promise for a potential treatment for hemophilia and other bleeding disorders.
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, Abramson Research Center, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Paris
authors.initials: P
authors.lastname: Margaritis
authors.forename: Valder R
authors.initials: VR
authors.lastname: Arruda
authors.forename: Majed
authors.initials: M
authors.lastname: Aljamali
authors.forename: Rodney M
authors.initials: RM
authors.lastname: Camire
authors.forename: Alexander
authors.initials: A
authors.lastname: Schlachterman
authors.forename: Katherine A
authors.initials: KA
authors.lastname: High
mesh_terms: D000818:Animals; D015942:Factor VIIa / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy; D006467:Hemophilia A / Q000628:therapy*; D002836:Hemophilia B / Q000628:therapy; D006801:Humans; D051379:Mice; D013997:Time Factors
chemical_list: D015942:Factor VIIa