title: Advances in gene therapy using factor VIIa in hemophilia.
abstract: The development of recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) has provided an effective, alternative treatment strategy for hemophilia patients with inhibitors. However, its short half-life necessitates frequent infusions and results in high treatment costs. One potential solution to this problem may lie in the use of FVIIa gene transfer, which would achieve long-lasting therapeutic levels of expression from a single injection. Studies in animal models have shown that a recombinant adeno-associated viral vector can be used to insert both murine and human FVIIa into murine liver. Following FVIIa gene transfer, mice with hemophilia B demonstrated a long-term, dose-dependent increase in circulating levels of FVIIa, reduced prothrombin time, and correction of activated partial thromboplastin time into the normal range. In addition, blood loss following a modified tail-clip assay was significantly reduced. Ongoing studies in mice engineered to express a wide range of FVIIa levels aim to analyze organ histology and evaluate long-term survival, reproductive fitness, and real-time in vivo clot formation in the microvasculature. These studies are expanding our knowledge of the effects of continuously expressed rFVIIa, and it is hoped that they may eventually provide a new avenue for treatment of hemophilia.
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Paris
authors.initials: P
authors.lastname: Margaritis
authors.forename: Katherine A
authors.initials: KA
authors.lastname: High
mesh_terms: D000818:Animals; D000229:Dependovirus; D004195:Disease Models, Animal; D005167:Factor VII / Q000235:genetics* / Q000378:metabolism; D015942:Factor VIIa; D018390:Gene Targeting / Q000379:methods; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D002836:Hemophilia B / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D005167:Factor VII; C103587:recombinant FVIIa; D015942:Factor VIIa