title: Factor VIII ectopically targeted to platelets is therapeutic in hemophilia A with high-titer inhibitory antibodies.
abstract: Inhibitory immune response to exogenously infused factor VIII (FVIII) is a major complication in the treatment of hemophilia A. Generation of such inhibitors has the potential to disrupt gene therapy for hemophilia A. We explore what we believe to be a novel approach to overcome this shortcoming. Human B-domain-deleted FVIII (hBDDFVIII) was expressed under the control of the platelet-specific alphaIIb promoter in platelets of hemophilic (FVIIInull) mice to create 2bF8trans mice. The FVIII transgene product was stored in platelets and released at the site of platelet activation. In spite of the lack of FVIII in the plasma of 2bF8trans mice, the bleeding phenotype of FVIIInull mice was corrected. More importantly, the bleeding phenotype was corrected in the presence of high inhibitory antibody titers introduced into the mice by infusion or by spleen cell transfer from recombinant hBDDFVIII-immunized mice. Our results demonstrate that this approach to the targeted expression of FVIII in platelets has the potential to correct hemophilia A, even in the presence of inhibitory immune responses to infused FVIII.
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Department of Pediatrics, Medical College of Wisconsin, and Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, Wisconsin 53226, USA.
authors.forename: Qizhen
authors.initials: Q
authors.lastname: Shi
authors.forename: David A
authors.initials: DA
authors.lastname: Wilcox
authors.forename: Scot A
authors.initials: SA
authors.lastname: Fahs
authors.forename: Hartmut
authors.initials: H
authors.lastname: Weiler
authors.forename: Clive W
authors.initials: CW
authors.lastname: Wells
authors.forename: Brian C
authors.initials: BC
authors.lastname: Cooley
authors.forename: Drashti
authors.initials: D
authors.lastname: Desai
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Morateck
authors.forename: Jack
authors.initials: J
authors.lastname: Gorski
authors.forename: Robert R
authors.initials: RR
authors.lastname: Montgomery
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D001792:Blood Platelets / Q000502:physiology*; D005169:Factor VIII / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use*; D015316:Genetic Therapy; D006467:Hemophilia A / Q000235:genetics / Q000276:immunology / Q000628:therapy; D006487:Hemostasis / Q000502:physiology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D015539:Platelet Activation; D019076:Transgenes; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D000906:Antibodies; D014841:von Willebrand Factor; D005169:Factor VIII