Factor VIII ectopically targeted to platelets is therapeutic in hemophilia A with high-titer inhibitory antibodies
Factor VIII ectopically targeted to platelets is therapeutic in hemophilia A with high-titer inhibitory antibodies
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DOI：
10.1172/jci28416
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发表时间：
2006-07-01
影响因子：
15.9
通讯作者：
Montgomery, Robert R.
中科院分区：
文献类型：
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作者：
Shi, Qizhen;Wilcox, David A.;Montgomery, Robert R.
对外源性输注因子 VIII (FVIII) 的抑制性免疫反应是治疗 A 型血友病的一个主要并发症。此类抑制剂的产生有可能破坏 A 型血友病的基因治疗。我们探索一种我们认为可以克服这一缺点的新方法。人 B 结构域缺失的 FVIII (hBDDFVIII) 在血友病 (FVIIInull) 小鼠血小板中血小板特异性 α IIb 启动子的控制下表达，以产生 2bF8(反式) 小鼠。 FVIII转基因产物储存在血小板中并在血小板活化部位释放。尽管2bF8(反式)小鼠血浆中缺乏FVIII，但FVIII-H小鼠的出血表型得到纠正。更重要的是，在通过输注或通过重组 hBDDFVIII 免疫小鼠的脾细胞转移引入小鼠体内的高抑制性抗体滴度的存在下，出血表型得到纠正。我们的结果表明，这种在血小板中靶向表达 FVIII 的方法有可能纠正 A 型血友病，即使存在对输注的 FVIII 的抑制性免疫反应。
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 alpha IIb promoter in platelets of hemophilic (FVIIInull) mice to create 2bF8(trans) 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 2bF8(trans) mice, the bleeding phenotype of FVIII-H 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.