title: Platelet-targeted gene therapy with human factor VIII establishes haemostasis in dogs with haemophilia A.
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.
authors.affiliation: 1] Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA [2] Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, Wisconsin 53226, USA [3] MACC Fund Research Center, Milwaukee, Wisconsin 53226, USA.
authors.forename: Lily M
authors.initials: LM
authors.lastname: Du
authors.forename: Paquita
authors.initials: P
authors.lastname: Nurden
authors.forename: Alan T
authors.initials: AT
authors.lastname: Nurden
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Nichols
authors.forename: Dwight A
authors.initials: DA
authors.lastname: Bellinger
authors.forename: Eric S
authors.initials: ES
authors.lastname: Jensen
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Haberichter
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Merricks
authors.forename: Robin A
authors.initials: RA
authors.lastname: Raymer
authors.forename: Juan
authors.initials: J
authors.lastname: Fang
authors.forename: Sevasti B
authors.initials: SB
authors.lastname: Koukouritaki
authors.forename: Paula M
authors.initials: PM
authors.lastname: Jacobi
authors.forename: Troy B
authors.initials: TB
authors.lastname: Hawkins
authors.forename: Kenneth
authors.initials: K
authors.lastname: Cornetta
authors.forename: Qizhen
authors.initials: Q
authors.lastname: Shi
authors.forename: David A
authors.initials: DA
authors.lastname: Wilcox
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D004283:Dog Diseases / Q000235:genetics / Q000628:therapy*; D004285:Dogs; D005169:Factor VIII / Q000235:genetics*; D005786:Gene Expression Regulation / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods / Q000662:veterinary*; D006467:Hemophilia A / Q000628:therapy / Q000662:veterinary*; D006487:Hemostasis; D006801:Humans; D039421:Integrin alpha2 / Q000235:genetics / Q000378:metabolism*
chemical_list: C056564:ITGA2B protein, human; D039421:Integrin alpha2; D005169:Factor VIII