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Factor VIII ectopically targeted to platelets is therapeutic in hemophilia A with high-titer inhibitory antibodies
Qizhen Shi, … , Jack Gorski, Robert R. Montgomery
Qizhen Shi, … , Jack Gorski, Robert R. Montgomery
Published July 3, 2006
Citation Information: J Clin Invest. 2006;116(7):1974-1982. https://doi.org/10.1172/JCI28416.
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Research Article Hematology Article has an altmetric score of 12

Factor VIII ectopically targeted to platelets is therapeutic in hemophilia A with high-titer inhibitory antibodies

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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 αIIb 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

Qizhen Shi, David A. Wilcox, Scot A. Fahs, Hartmut Weiler, Clive W. Wells, Brian C. Cooley, Drashti Desai, Patricia A. Morateck, Jack Gorski, Robert R. Montgomery

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Figure 4

Platelet-derived FVIII can function in the presence of FVIII inhibitory antibodies.

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Platelet-derived FVIII can function in the presence of FVIII inhibitory ...
(A) Dose response to rhBDDFVIII infusion in FVIIInull mice. When rhBDDFVIII was infused into FVIIInull mice and tail clip was performed, all FVIIInull mice survived tail clipping when infused to a final level of 0.02 U/ml rhBDDFVIII. When rhBDDFVIII was infused at the same concentration (0.02 U/ml) into FVIIInull mice that had been pre-injected with mouse inhibitor plasma, no FVIIInull mice with 25 or 250 BU/ml survived tail clipping. (B) Dose response to FVIII inhibitory antibody infusion in 2bF8trans mice. Different doses of inhibitor plasma from immunized FVIIInull mice were infused into 2bF8tg+/– mice. All mice survived tail clipping when infused with less than 25 BU/ml inhibitory plasma, and 7 of 8 survived with a titer of 250 BU/ml. (C) Tail clip survival test on the recipients of spleen cell transplantation. Sublethally irradiated 2bF8tg+/– or WT mice received spleen cells from immunized FVIIInull mice. Two weeks after transplantation, plasma was tested by inhibitor analysis and the tail clip survival test was performed. Transgenic 2bF8trans mice demonstrated enhanced tail clip survival even in the presence of a titer greater than 5,000 BU/ml. (D) Tail clip survival test of immunized 2bF8trans mice. Heterozygous 2bF8tg+/– mice were immunized with rhBDDFVIII (with adjuvant) by i.p. injection once. Two weeks after immunization, plasma was used for inhibitor quantitation and the tail clip survival test was performed. All immunized 2bF8trans mice survived tail clipping with a titer of 10–50 BU/ml.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 11 patents
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