Plerixafor enables safe, rapid, efficient mobilization of hematopoietic stem cells in sickle cell disease patients after exchange transfusion.
Plerixafor enables safe, rapid, efficient mobilization of hematopoietic stem cells in sickle cell disease patients after exchange transfusion.
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DOI：
10.3324/haematol.2017.184788
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发表时间：
2018-05
期刊：
影响因子：
10.1
通讯作者：
Cavazzana M
中科院分区：
文献类型：
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作者：
Lagresle-Peyrou C;Lefrère F;Magrin E;Ribeil JA;Romano O;Weber L;Magnani A;Sadek H;Plantier C;Gabrion A;Ternaux B;Félix T;Couzin C;Stanislas A;Tréluyer JM;Lamhaut L;Joseph L;Delville M;Miccio A;André-Schmutz I;Cavazzana M
镰状细胞病的特点是慢性贫血和血管闭塞危象，最终导致多器官损伤和过早死亡。造血干细胞移植是唯一的治疗方法，但它受到毒性和hla兼容供体的缺乏的限制。一种基于慢病毒校正的造血干细胞和祖细胞自体移植的基因治疗方法在一名患者中被证明是有效的。然而，骨髓环境和红细胞特性的改变阻碍了患者骨髓干细胞的采集和免疫选择。使用非格昔汀动员大量造血干细胞和祖细胞进入循环与镰状细胞患者的严重不良事件有关。因此，基因治疗方法的广泛应用需要开发替代的动员方法。我们建立了一项I/II期临床试验，其主要目的是评估单次注射Plerixafor对接受红细胞交换的镰状细胞患者的安全性，以降低血红蛋白S水平至30%以下。次要目的是衡量造血干细胞和祖细胞的动员和分离效率。未观察到不良事件。大量CD34+细胞被极快地动员起来。重要的是，被动员的细胞含有大量的造血干细胞，表达高水平的干性基因，并且在免疫缺陷小鼠中非常有效地移植。因此，Plerixafor可以安全地用于动员镰状细胞患者的造血干细胞；这一发现为基于基因添加和基因组编辑的治疗方法开辟了新的途径。Clinicaltrials.gov识别码：NCT02212535。
Sickle cell disease is characterized by chronic anemia and vaso-occlusive crises, which eventually lead to multi-organ damage and premature death. Hematopoietic stem cell transplantation is the only curative treatment but it is limited by toxicity and poor availability of HLA-compatible donors. A gene therapy approach based on the autologous transplantation of lentiviral-corrected hematopoietic stem and progenitor cells was shown to be efficacious in one patient. However, alterations of the bone marrow environment and properties of the red blood cells hamper the harvesting and immunoselection of patients’ stem cells from bone marrow. The use of Filgrastim to mobilize large numbers of hematopoietic stem and progenitor cells into the circulation has been associated with severe adverse events in sickle cell patients. Thus, broader application of the gene therapy approach requires the development of alternative mobilization methods. We set up a phase I/II clinical trial whose primary objective was to assess the safety of a single injection of Plerixafor in sickle cell patients undergoing red blood cell exchange to decrease the hemoglobin S level to below 30%. The secondary objective was to measure the efficiency of mobilization and isolation of hematopoietic stem and progenitor cells. No adverse events were observed. Large numbers of CD34+ cells were mobilized extremely quickly. Importantly, the mobilized cells contained high numbers of hematopoietic stem cells, expressed high levels of stemness genes, and engrafted very efficiently in immunodeficient mice. Thus, Plerixafor can be safely used to mobilize hematopoietic stem cells in sickle cell patients; this finding opens up new avenues for treatment approaches based on gene addition and genome editing. Clinicaltrials.gov identifier: NCT02212535.