Innovations in hematopoietic stem-cell mobilization: a review of the novel CXCR4 inhibitor motixafortide.
Innovations in hematopoietic stem-cell mobilization: a review of the novel CXCR4 inhibitor motixafortide.
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DOI：
10.1177/20406207231174304
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发表时间：
2023
影响因子：
3.4
通讯作者：
DiPersio, John F.
中科院分区：
文献类型：
--
作者：
Crees, Zachary D.;Rettig, Michael P.;DiPersio, John F.
关键词：
造血干细胞移植（HCT）和基于干细胞的基因治疗依赖于收集足够的CD34+造血干细胞和祖细胞（HSPCs）的能力，通常通过外周血动员。常用的HSPC动员方案包括单药粒细胞集落刺激因子（G-CSF）、普利沙福、化疗或这些药物的组合。然而，这些方案通常需要多天的注射和白细胞分离程序，以收集用于HCT的足够的HSPCs（最小值= 2 × 106 CD34+细胞/kg；最佳值= 5-6 × 106 CD34+细胞/kg）。此外，考虑到成功的基因编辑和制造需要更高的HSPC数量，这些方案经常产生基于HSPC的基因编辑疗法的CD34+ HSPC数量不理想。同时，G-CSF与骨痛等常见不良事件以及罕见但可能危及生命的脾破裂风险增加有关。此外，G-CSF在镰状细胞病患者中是不安全的，镰状细胞病患者是一个可能受益于自体hspc基因编辑疗法的关键患者群体，在这些患者中，G-CSF与严重血管闭塞和血栓形成事件的不可接受的发生率相关。Motixafortide是一种新型的CXCR4抑制剂，具有较长的体内活性（bbb48小时），在临床前和临床试验中已被证明可以快速动员大量的HSPCs为HCT做准备，同时通过免疫表型和单细胞RNA表达谱优先动员更多的原始HSPCs。在这篇综述中，我们介绍了干细胞动员的历史和新动员策略的最新创新，特别关注motixafortide的开发，motixafortide是一种长效CXCR4抑制剂，作为一种新的HSPC动员剂。
Hematopoietic stem-cell transplantation (HCT) and stem-cell–based gene therapies rely on the ability to collect sufficient CD34+ hematopoietic stem and progenitor cells (HSPCs), typically via peripheral blood mobilization. Commonly used HSPC mobilization regimens include single-agent granulocyte colony-stimulating factor (G-CSF), plerixafor, chemotherapy, or a combination of these agents. These regimens, however, frequently require multiple days of injections and leukapheresis procedures to collect adequate HSPCs for HCT (minimum = >2 × 106 CD34+ cells/kg; optimal = 5–6 × 106 CD34+ cells/kg). In addition, these regimens frequently yield suboptimal CD34+ HSPC numbers for HSPC-based gene-edited therapies, given the significantly higher HSPC number needed for successful gene-editing and manufacturing. Meanwhile, G-CSF is associated with common adverse events such as bone pain as well as an increased risk of rare but potentially life-threatening splenic rupture. Moreover, G-CSF is unsafe in patients with sickle-cell disease, a key patient population that may benefit from autologous HSPC-based gene-edited therapies, where it has been associated with unacceptable rates of serious vaso-occlusive and thrombotic events. Motixafortide is a novel CXCR4 inhibitor with extended in vivo activity (>48 h) that has been shown in preclinical and clinical trials to rapidly mobilize robust numbers of HSPCs in preparation for HCT, while preferentially mobilizing increased numbers of more primitive HSPCs by immunophenotyping and single-cell RNA expression profiling. In this review, we present a history of stem-cell mobilization and update of recent innovations in novel mobilization strategies with a specific focus on the development of motixafortide, a long-acting CXCR4 inhibitor, as a novel HSPC mobilizing agent.
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DOI：
10.1073/pnas.89.7.2804
发表时间：
1992-04-01
影响因子：
11.1
作者：
BAUM, CM;WEISSMAN, IL;PEAULT, B
通讯作者：
PEAULT, B
影响因子：
4.5
作者：
Fitzhugh, Courtney D.;Hsieh, Matthew M.;Tisdale, John F.
通讯作者：
Tisdale, John F.
影响因子：
6.2
作者：
Christopher, Matthew J.;Link, Daniel C.
通讯作者：
Link, Daniel C.
影响因子：
64.8
作者：
BECKER, AJ;TILL, JE;MCCULLOCH, EA
通讯作者：
MCCULLOCH, EA
影响因子：
45.3
作者：
DiPersio, John F.;Micallef, Ivana N.;Calandra, Gary
通讯作者：
Calandra, Gary