Factor VIII ectopically targeted to platelets is therapeutic in hemophilia A with high-titer inhibitory antibodies. J Clin Invest 2006 Jul;116(7):1974-82
Date
07/11/2006Pubmed ID
16823491Pubmed Central ID
PMC1483176DOI
10.1172/JCI28416Scopus ID
2-s2.0-33745864802 (requires institutional sign-in at Scopus site) 155 CitationsAbstract
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.
Author List
Shi Q, Wilcox DA, Fahs SA, Weiler H, Wells CW, Cooley BC, Desai D, Morateck PA, Gorski J, Montgomery RRAuthors
Robert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of WisconsinQizhen Shi MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin
Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of Wisconsin
David A. Wilcox PhD Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAntibodies
Blood Platelets
Factor VIII
Genetic Therapy
Hemophilia A
Hemostasis
Humans
Mice
Mice, Transgenic
Phenotype
Platelet Activation
Transgenes
von Willebrand Factor
