Platelet Gene Therapy by Lentiviral Gene Delivery to Hematopoietic Stem Cells Restores Hemostasis and Induces Humoral Immune Tolerance in FIXnull Mice
Platelet Gene Therapy by Lentiviral Gene Delivery to Hematopoietic Stem Cells Restores Hemostasis and Induces Humoral Immune Tolerance in FIXnull Mice
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DOI：
10.1038/mt.2013.197
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发表时间：
2014-01-01
影响因子：
12.4
通讯作者：
Shi, Qizhen
中科院分区：
文献类型：
--
作者：
Chen, Yingyu;Schroeder, Jocelyn A.;Shi, Qizhen
在这里，我们开发了一种临床上可翻译的血小板基因治疗血友病B的方法。通过移植用2bF 9慢病毒（LV）转导的造血干细胞（HSC）引入血小板靶向FIX（2bF 9）表达。在接受2bF 9 LV转导的HSC的FIX缺失小鼠中获得了持续治疗水平的血小板-FIX表达。在转导的受体中，约6-39%的血小板表达FIX，这足以在剪尾模型中挽救FIX缺失小鼠的出血素质。序贯骨髓移植表明，血小板-FIX表达在第二次受体持续，导致表型校正。值得注意的是，没有一个转导受体在血小板基因治疗后产生抗FIX抗体。在用rhFIX激发后，9个受体中只有1个产生了低滴度的抑制性抗体（1.6 BU/ml）。这些数据表明，血小板基因治疗不仅可以恢复止血，而且还可以诱导血友病B小鼠的免疫耐受，表明这种方法可能是一个有前途的策略，血友病B在人类的基因治疗。
Here, we developed a clinically translatable platelet gene therapy approach for hemophilia B. Platelet-targeted FIX (2bF9) expression was introduced by transplantation of hematopoietic stem cells (HSCs) transduced with 2bF9 lentivirus (LV). Sustained therapeutic levels of platelet-FIX expression were obtained in FIXnull mice that received 2bF9 LV-transduced HSCs. Approximately 6-39% of the platelets expressed FIX in the transduced recipients, which was sufficient to rescue the bleeding diathesis in FIXnull mice in tail clipping models. Sequential bone marrow transplantation demonstrated that platelet-FIX expression in the secondary recipients was sustained, leading to phenotypic correction. Notably, none of the transduced recipients developed anti-FIX antibodies after platelet gene therapy. Only one of the nine recipients developed a low titer of inhibitory antibodies (1.6 BU/ml) after challenge with rhFIX. These data suggest that platelet gene therapy can not only restore hemostasis but also induce immune tolerance in hemophilia B mice, indicating that this approach may be a promising strategy for gene therapy of hemophilia B in humans.