Platelet-targeted gene therapy with human factor VIII establishes haemostasis in dogs with haemophilia A

Lily M. Du, Paquita Nurden, Alan T. Nurden, Timothy C. Nichols, Dwight A. Bellinger, Eric S. Jensen, Sandra L. Haberichter, Elizabeth Merricks, Robin A. Raymer, Juan Fang, Sevasti B. Koukouritaki, Paula M. Jacobi, Troy B. Hawkins, Kenneth Cornetta, Qizhen Shi and David A. Wilcox ()
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Lily M. Du: Medical College of Wisconsin
Paquita Nurden: Plateforme Technologique et d’Innovation Biomédicale, Hôpital Xavier Arnozan
Alan T. Nurden: Plateforme Technologique et d’Innovation Biomédicale, Hôpital Xavier Arnozan
Timothy C. Nichols: University of North Carolina
Dwight A. Bellinger: University of North Carolina
Eric S. Jensen: Medical College of Wisconsin
Sandra L. Haberichter: Medical College of Wisconsin
Elizabeth Merricks: University of North Carolina
Robin A. Raymer: University of North Carolina
Juan Fang: Medical College of Wisconsin
Sevasti B. Koukouritaki: Medical College of Wisconsin
Paula M. Jacobi: Blood Research Institute, BloodCenter of Wisconsin
Troy B. Hawkins: Indiana University School of Medicine
Kenneth Cornetta: Indiana University School of Medicine
Qizhen Shi: Medical College of Wisconsin
David A. Wilcox: Medical College of Wisconsin

Nature Communications, 2013, vol. 4, issue 1, 1-11

Abstract: Abstract It is essential to improve therapies for controlling excessive bleeding in patients with haemorrhagic disorders. As activated blood platelets mediate the primary response to vascular injury, we hypothesize that storage of coagulation Factor VIII within platelets may provide a locally inducible treatment to maintain haemostasis for haemophilia A. Here we show that haematopoietic stem cell gene therapy can prevent the occurrence of severe bleeding episodes in dogs with haemophilia A for at least 2.5 years after transplantation. We employ a clinically relevant strategy based on a lentiviral vector encoding the ITGA2B gene promoter, which drives platelet-specific expression of human FVIII permitting storage and release of FVIII from activated platelets. One animal receives a hybrid molecule of FVIII fused to the von Willebrand Factor propeptide-D2 domain that traffics FVIII more effectively into α-granules. The absence of inhibitory antibodies to platelet-derived FVIII indicates that this approach may have benefit in patients who reject FVIII replacement therapies. Thus, platelet FVIII may provide effective long-term control of bleeding in patients with haemophilia A.

Date: 2013
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DOI: 10.1038/ncomms3773

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