Successful treatment of canine hemophilia by continuous expression of canine FVIIa

Author:

Margaritis Paris1,Roy Elise1,Aljamali Majed N.1,Downey Harre D.1,Giger Urs2,Zhou Shangzhen1,Merricks Elizabeth3,Dillow Aaron3,Ezban Mirella4,Nichols Timothy C.3,High Katherine A.15

Affiliation:

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

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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