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Blood, 16 April 2009, Vol. 113, No. 16, pp. 3682-3689. Prepublished online as a Blood First Edition Paper on December 23, 2008; DOI 10.1182/blood-2008-07-168377. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-07-168377v1 113/16/3682    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Margaritis, P. Articles by High, K. A. Search for Related Content PubMed PubMed Citation Articles by Margaritis, P. Articles by High, K. A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Successful treatment of canine hemophilia by continuous expression of canine FVIIa Paris Margaritis1, Elise Roy1, Majed N. Aljamali1, Harre D. Downey1, Urs Giger2, Shangzhen Zhou1, Elizabeth Merricks3, Aaron Dillow3, Mirella Ezban4, Timothy C. Nichols3, and Katherine A. High1,5 1 Division of Hematology, Children's Hospital of Philadelphia, PA; 2 Section of Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia; 3 Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill; 4 Biopharmaceutical Research Unit, Novo Nordisk A/S, Måløv, Denmark; and 5 Howard Hughes Medical Institute, Children's Hospital of Philadelphia, PA 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: FVIIa gene delivery: potential treatment for hemophilia? John H. McVey Blood 2009 113: 3649-3650. [Full Text] [PDF] This article has been cited by other articles: J. H. McVey FVIIa gene delivery: potential treatment for hemophilia? Blood, April 16, 2009; 113(16): 3649 - 3650. [Full Text] [PDF]

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