Factor IX ectopically expressed in platelets can be stored in α-granules and corrects the phenotype of hemophilia B mice
Factor IX ectopically expressed in platelets can be stored in α-granules and corrects the phenotype of hemophilia B mice
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DOI：
10.1182/blood-2009-11-255612
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发表时间：
2010-08-26
期刊：
影响因子：
20.3
通讯作者：
Montgomery, Robert R.
中科院分区：
文献类型：
--
作者：
Zhang, Guowei;Shi, Qizhen;Montgomery, Robert R.
我们在血友病B小鼠模型中开发了2bF 9转基因小鼠，在血小板特异性整合素α II B启动子的控制下表达人因子IX（FIX），以确定在巨核细胞中异位表达FIX是否能够使FIX储存在血小板α颗粒中并纠正小鼠血友病B表型。通过抗原和活性测定在2bF 9转基因小鼠的血小板和血浆中检测到FIX。血液中约90%的总FIX储存在血小板中，其中大部分在血小板活化时可释放。免疫组化显示FIX在血小板和巨核细胞中表达，并储存在α颗粒中。所有2bF 9转基因小鼠在剪尾后均存活，表明血小板源性FIX使血友病B小鼠模型中的止血正常化。这种保护作用可以通过骨髓移植或血小板输注来转移。然而，与我们的血小板FVIII经验不同，在存在抗FIX抑制性抗体的情况下，血小板源性FIX的疗效有限。这些结果表明，可释放的FIX可在血小板α颗粒中表达和储存，血小板衍生的FIX可纠正血友病B小鼠的出血表型。我们的研究表明，将FIX表达靶向血小板可能是血友病B的一种新的基因治疗策略。（血。2010; 116（8）：1235-1243）
We developed 2bF9 transgenic mice in a hemophilia B mouse model with the expression of human factor IX (FIX) under control of the platelet-specific integrin alpha IIb promoter, to determine whether ectopically expressing FIX in megakaryocytes can enable the storage of FIX in platelet alpha-granules and corrects the murine hemophilia B phenotype. FIX was detected in the platelets and plasma of 2bF9 transgenic mice by both antigen and activity assays. Approximately 90% of total FIX in blood was stored in platelets, most of which is releasable on activation of platelets. Immunostaining demonstrated that FIX was expressed in platelets and megakaryocytes and stored in alpha-granules. All 2bF9 transgenic mice survived tail clipping, suggesting that platelet-derived FIX normalizes hemostasis in the hemophilia B mouse model. This protection can be transferred by bone marrow transplantation or platelet transfusion. However, un-like our experience with platelet FVIII, the efficacy of platelet-derived FIX was limited in the presence of anti-FIX inhibitory antibodies. These results demonstrate that releasable FIX can be expressed and stored in platelet alpha-granules and that platelet-derived FIX can correct the bleeding phenotype in hemophilia B mice. Our studies suggest that targeting FIX expression to platelets could be a new gene therapy strategy for hemophilia B. (Blood. 2010; 116(8): 1235-1243)