波士顿儿童医院Pietro Genovese团队宣布他们的研究开发出了通过表位编辑进行非遗传毒性移植和体内选择。这一研究成果发表在2026年7月8日出版的国际学术期刊《自然》上。

为了解决这个问题，该课题组研究人员发现KIT细胞外结构域的氨基酸变化会破坏两种治疗性单克隆抗体的结合，从而损害干细胞因子（SCF）介导的信号传导，而不影响KIT的表达或功能。课题组人员利用腺嘌呤碱基编辑或引物编辑有效地在HSPCs中引入这些突变，并将它们与破坏BCL11A红系增强子相结合，以促进胎儿血红蛋白（HbF）的表达，这是几种血红蛋白病的治疗方法。这种策略使基因工程细胞的体内共选择能够达到为镰状细胞病和β-地中海贫血患者提供治疗益处所需的阈值。

该研究团队在体外和体内展示了在KIT单克隆抗体的选择压力下，KIT在BCL11A多重编辑造血中逐渐富集。该课题组研究人员报告，通过慢病毒条形码文库评估，抗KIT方案的延长治疗可以在避免克隆选择的同时获得更好的体内富集。最后，通过克服单克隆抗体药代动力学的局限性，表位编辑使新的造血替代方案不受靶向移植物消除的限制，允许长时间的免疫调节，最大限度地提高造血生态位清除，而无需化疗或单克隆抗体洗脱。

据了解，遗传毒性移植前调节的短期和长期影响仍然是造血干细胞/祖细胞（HSPC）移植和基因治疗广泛应用的障碍。尽管针对KIT的单克隆抗体已被提出作为化疗或放疗的替代方案，但由于存在耗尽移植造血干细胞的风险，其药代动力学阻碍了临床应用。

附：英文原文

Title: Non-genotoxic transplantation and in vivo selection through epitope editing

Author: Casirati, Gabriele, Cosentino, Andrea, Freschi, Marta, Zeng, Jing, Mucci, Adele, Levesque, Sbastien, Neri, Nola, Drago, Enrico, Carzaniga, Viola, Romano, Francesco, Katta, Varun, Matsubara, Azusa, Li, Yichao, Mahmoud, Mohammed S., Chvez-Navarro, Moiss, Brendel, Christian, Manis, John P., Tsai, Shengdar, Pellin, Danilo, Bauer, Daniel, Genovese, Pietro

Issue&Volume: 2026-07-08

Abstract: The short-term and long-term effects of genotoxic pre-transplant conditioning remain barriers to the broader application of haematopoietic stem/progenitor cell (HSPC) transplantation and gene therapies1,2,3,4. Although monoclonal antibodies targeting KIT have been proposed as alternatives to chemotherapy or radiotherapy5,6,7, their pharmacokinetics hinder clinical applications owing to the risk of depleting transplanted HSPCs. Here, to address this issue, we identified amino acid changes in the extracellular domain of KIT that disrupt the binding of two therapeutic monoclonal antibodies8,9, which impair stem cell factor (SCF)-mediated signalling without affecting KIT expression or functionality. We exploited adenine base editing10 or prime editing11 to efficiently introduce these mutations in HSPCs and combined them with the disruption of the BCL11A erythroid enhancer to promote expression of fetal haemoglobin (HbF)12,13, a therapeutic approach for several haemoglobinopathies. This strategy enables in vivo co-selection of gene-engineered cells to reach the threshold required to provide therapeutic benefit in patients affected by sickle cell disease and β-thalassaemia. We show progressive enrichment of KIT plus BCL11A multiplex-edited haematopoiesis under selective pressure with KIT monoclonal antibody, in vitro and in vivo. We report that extended treatment with anti-KIT regimens leads to superior in vivo enrichment while avoiding clonal selection, as assessed by a lentiviral barcoded library. Finally, by overcoming the limitations of monoclonal antibody pharmacokinetics, epitope editing enables novel haematopoietic replacement regimens that are not limited by on-target graft elimination, allowing prolonged immune-based conditioning that maximizes haematopoietic niche clearance without chemo-radiotherapy or monoclonal antibody wash-out.

DOI: 10.1038/s41586-026-10737-8

Source: https://www.nature.com/articles/s41586-026-10737-8