Repele Andrea, Pande Dnyanada, Enstrom Mark R, Perez Anai Michelle, Cui Margaret, Madhu Ravishankar, Nelson Veronica, Kiem Hans-Peter, Radtke Stefan
Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Division of Hematology and Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
Mol Ther Methods Clin Dev. 2025 Aug 13;33(3):101558. doi: 10.1016/j.omtm.2025.101558. eCollection 2025 Sep 11.
Autologous hematopoietic stem cell (HSC) gene therapy has gone through remarkable advancements in recent years, especially for the treatment of sickle cell disease (SCD). However, the collection of HSCs from SCD patients requires unique considerations, as granulocyte colony-stimulating factor (G-CSF)-mediated mobilization is contraindicated, and plerixafor-only mobilization is highly variable. Consequently, alternative mobilization regimens that are safe for SCD patients and generate better cell yields are desirable for SCD HSC gene therapy. Here, we evaluated a combination of plerixafor (AMD3100, a CXCR4 antagonist) with GroβT (MGTA-145/GroβT, a CXCR2 agonist) against the current gold-standard G-CSF for HSC gene therapy in nonhuman primates (NHPs) for HSC mobilization, leukapheresis, gene editing to reactivate fetal hemoglobin, and transplantation. AMD3100/GroβT rapidly and reliably mobilized phenotypically primitive HSCs within hours even in a G-CSF non-responder. Average CD34/CD90 frequency in the blood and yields after enrichment were comparable in both mobilization regimens. Rapid recovery and robust multilineage long-term engraftment of gene-modified HSCs was achieved in the bone marrow and blood of animals. In summary, AMD3100/GroβT allows highly efficient and reliable mobilization of HSCs, providing a G-CSF-free regimen specifically for SCD but also any other hematological disease or disorder treatable with HSC gene therapy.
近年来，自体造血干细胞（HSC）基因治疗取得了显著进展，尤其是在镰状细胞病（SCD）的治疗方面。然而，从SCD患者中采集HSCs需要特殊考虑，因为粒细胞集落刺激因子（G-CSF）介导的动员是禁忌的，而仅使用普乐沙福进行动员的效果差异很大。因此，对于SCD HSC基因治疗来说，需要一种对SCD患者安全且能产生更好细胞产量的替代动员方案。在此，我们评估了普乐沙福（AMD3100，一种CXCR4拮抗剂）与GroβT（MGTA-145/GroβT，一种CXCR2激动剂）联合使用，以替代目前用于非人类灵长类动物（NHPs）HSC基因治疗中HSC动员、白细胞分离、基因编辑以重新激活胎儿血红蛋白和移植的金标准G-CSF。即使在对G-CSF无反应的情况下，AMD3100/GroβT也能在数小时内快速且可靠地动员表型原始的HSCs。两种动员方案在血液中的平均CD34/CD90频率以及富集后的产量相当。在动物的骨髓和血液中实现了基因修饰的HSCs的快速恢复和强大的多谱系长期植入。总之，AMD3100/GroβT能够高效且可靠地动员HSCs，提供了一种无G-CSF的方案，专门用于SCD，也适用于任何其他可用HSC基因治疗的血液疾病或病症。
