July 2026
Lara C. Pullen
Original article: https://ashpublications.org/ashclinicalnews/news/9329/Base-Editing-Contributes-to-Meaningful-HbF
Both transformer Base Editing (tBE) and CRISPR-Cas9 nuclease-mediated editing can induce precise, targeted base substitutions in human hematopoietic stem cells. tBE has an advantage over CRISPR-Cas9 in that it does not generate DNA double-strand breaks (DSBs), thereby avoiding the consequent p53-mediated stress and apoptosis. This difference has been demonstrated in preclinical studies, which have shown that tBE-modified hematopoietic stem and progenitor cells (HSPCs) exhibit reduced cell-cycle arrest and apoptosis, along with enhanced proliferative capacity compared with Cas9-edited cells.
Now, a team of researchers in China has extended their preclinical findings into the clinic, and the investigators report that an infusion of autologous CD34+ cells modified using a tBE at clinical scale (CS-101) can lead to rapid and sustained increases in both total hemoglobin and fetal hemoglobin (HbF) levels in patients with beta thalassemia, as well as early and enduring transfusion independence. Yongrong Lai, MD, PhD, professor of hematology at the First Affiliated Hospital of Guangxi Medical University in China, and colleagues published these findings in Nature.
The investigators sought to determine if cytosine base editing mediated by tBE at BCL11A binding motifs within the HBG1/2 promoter regions can reactivate HbF. Their paper describes how all five patients infused with CS-101, including three with the β0/β0 of β0/β0-like genotype, discontinued transfusions within one month. The patients’ mean HbF levels reached 11.5 ± 0.9 g/dL at three months post-treatment and 12.9 ± 1.6 g/dL at 15 months.
Senior investigator Jia Chen, PhD, director of the Gene Editing Center at ShanghaiTech University in China, explained, "Our tBE-based approach largely avoids DSBs, which may contribute to improved safety and more efficient hematopoietic recovery." The median time to neutrophil engraftment was 16 days, and the median time to platelet engraftment was 25 days.
The CS-101 infusion had adverse effects that were largely consistent with those typically associated with busulfan myeloablative conditioning. "The 'lock-and-key' design of tBE restricts editing activity to the intended target sites while minimizing off-target activity," Dr. Chen explained. "Consistent with this, no detectable off-target editing was observed in our cohort, supporting a favorable long-term safety profile."
The researchers found that the base-editing efficiencies of the BCL11A binding motif in the HBG1/2 promoters remained stable in both peripheral blood mononuclear cells (PBMCs) and bone marrow cells over the follow-up period and that even a single cytosine edit was sufficient to disrupt BCL11A binding at these sites.
"We found that a cytosine editing frequency of greater than about 30% at the HBG1/2 promoter was sufficient to drive robust HbF production," Dr. Chen said. "For example, Patient 3 exhibited editing frequencies of approximately 30% in both peripheral blood and bone marrow cells, while Patient 5 showed about 50% editing. Despite this difference, Patient 3 maintained HbF levels of about 12.8 g/dL at one-year post-treatment, compared with about 11 g/dL in Patient 5."
When the investigators further analyzed editing across the four BCL11A binding motifs present in the diploid genome (two HBG1 and two HBG2 alleles) at the single-cell level, they found that approximately one-third of CD34+ HSPCs remained unedited in treated patients. Moreover, the base-editing spectra from the study participants were similar across all five patients and remained stable throughout the follow-up period. Dr. Chen concluded from this that erythroid cells with one or more edited motifs (ranging from one to three) can contribute meaningfully to HbF production.
The authors cited limitations to the study, including a small patient cohort, a single-center design, and a relatively short follow-up period (median 23.0 months after CS-101 transfusion).
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Lai Y, Liu R, Wang L, et al. Clinical application of base editing for treating β-thalassemia. Nature. Published online April 8, 2026. doi: 10.1038/s41586-026-10342-9.
【全文翻译】
碱基编辑疗法显著提升β-地中海贫血患者HbF水平
Lara C. Pullen 2026/07
变形式碱基编辑技术（transformer Base Editing，tBE）和CRISPR-Cas9核酸酶介导的基因编辑技术均能够在人类造血干细胞中实现精准的靶向碱基转换。然而，与CRISPR-Cas9相比，tBE的优势在于其不会产生DNA双链断裂（DNA double-strand breaks, DSBs），从而避免由此引发的p53介导的细胞应激反应和细胞凋亡。这一差异已在临床前研究中得到证实，研究表明，与Cas9编辑的细胞相比，经tBE编辑的造血干细胞及祖细胞（hematopoietic stem and progenitor cells, HSPCs）表现出更低水平的细胞周期停滞和细胞凋亡，同时具有更强的增殖能力。
如今，中国研究团队已将这一临床前研究成果推进至临床试验阶段。临床数据显示，β-地中海贫血患者在接受tBE编辑的自体CD34+细胞（CS-101注射液）回输后，总血红蛋白和胎儿血红蛋白（fetal hemoglobin, HbF）水平快速提升且持续高水平表达，迅速摆脱输血依赖。该研究由广西医科大学第一附属医院血液科教授赖永榕团队与正序生物、上海科技大学、复旦大学、上海临床研究中心等多家单位合作开展，相关研究成果发表于国际学术期刊Nature。
研究人员旨在评估，利用tBE靶向编辑HBG1/2启动子区域内BCL11A结合基序，是否能够重新激活HbF表达。文章展示了接受CS-101注射液治疗的5例患者的临床结果，其中包括3例β⁰/β⁰或β⁰/β⁰样基因型患者。所有患者均在治疗后1个月内摆脱输血依赖。治疗后3个月，HbF浓度平均为11.5 ± 0.9 g/dL；治疗后15个月，HbF浓度平均为12.9 ± 1.6 g/dL。
文章的主要研究者、上海科技大学生命科学与技术学院教授、基因编辑中心主任陈佳博士表示：“我们基于tBE开发的原创碱基编辑疗法，能够有效避免DNA双链断裂，这将有助于提升治疗的安全性，并更快速地实现造血功能的恢复。”临床数据显示，患者中性粒细胞植入的中位时间为16天，血小板植入的中位时间为25天。
CS-101注射液安全性表现良好，其不良反应与传统造血干细胞移植治疗中白消安清髓预处理方案常见的不良反应一致，未出现产品相关的不良事件。陈佳教授表示，tBE采用“锁-钥匙”（lock-and-key）的设计，只有在靶向位点时编辑功能才能“解锁”，而在非靶向位点时编辑功能失效，从而实现了高效无脱靶的精准编辑效果。此次临床数据也证实了这一点——所有受试者中均未检测到脱靶编辑，进一步验证了CS-101注射液具备良好的、持续的安全性。
随访期间，编辑效率在外周血和骨髓细胞中均保持稳定。同时，即使只进行一次编辑就足以破坏BCL11A与这些位点的结合。
“我们发现，当编辑效率达到约30%以上时，即可有效诱导HbF的高水平表达。”陈佳教授表示，“例如，患者3在外周血和骨髓细胞中的编辑效率均约为30%，而患者5的编辑效率约为50%。尽管两者编辑效率存在差异，但患者3在治疗一年后HbF水平仍维持约12.8 g/dL，而患者5约为11 g/dL。”
当研究人员进一步在单细胞水平分析二倍体基因组中4个BCL11A结合基序（包括两个HBG1等位基因和两个HBG2等位基因）的编辑情况时，他们发现，患者体内约三分之一的CD34+ HSPCs仍未被编辑。此外，5名患者的碱基编辑谱高度相似，并且在整个随访期间保持稳定。陈佳教授由此得出结论，携带一个或多个（范围为1至3个）编辑基序的红系细胞，均能够对HbF的表达作出重要贡献。”
作为一项初步临床研究，该试验采用单中心研究设计，入组数量有限，中位随访时间为回输后23.0个月。研究团队指出，上述特点提示仍需扩大样本量以进一步验证CS-101的长期疗效与安全性，而当前数据已展现出令人鼓舞的应用潜力。
*作者声明的利益冲突信息参见原始论文。
Lai Y, Liu R, Wang L, et al. Clinical application of base editing for treating β-thalassemia. Nature. Published online April 8, 2026. doi: 10.1038/s41586-026-10342-9.
原文链接：https://ashpublications.org/ashclinicalnews/news/9329/Base-Editing-Contributes-to-Meaningful-HbF
关于ASH:
美国血液学会（American Society of Hematology，ASH）成立于1958年，是全球规模最大的血液学专业组织，致力于推动血液疾病的研究、诊疗与防治。学会拥有来自全球近100个国家的超过18,000名会员，涵盖临床医生、科研人员及相关领域的专业人士。ASH每年12月举办全球血液学领域规模最大、最具影响力的学术年会，吸引来自100多个国家的近30,000名专家学者参会，交流血液系统疾病领域的前沿突破与临床进展。第67届ASH年会于2025年12月6～9日在美国奥兰多举办。
关于CS-101注射液:
CS-101注射液是由正序生物基于自主原创碱基编辑技术tBE开发的一款针对β-地中海贫血的体外碱基编辑药物，该疗法通过采集患者自体造血干细胞，利用tBE对患者自体造血干细胞中的HBG1/2启动子区域进行精准碱基编辑，模拟健康人群中天然存在的有益碱基突变，重新激活γ-珠蛋白的表达，重建血红蛋白的携氧功能，再将编辑后的造血干细胞回输至患者体内，使得患者自身血红蛋白浓度达到健康人水平，从而彻底摆脱输血依赖。
CS-101注射液已经在临床试验中成功治愈来自中国、老挝、马来西亚、巴基斯坦等国家的近20位β-地中海贫血患者，全部接受治疗的患者均已持续摆脱输血依赖达一年以上，首例患者已持续摆脱输血依赖超过31个月。2026年4月8日，CS-101注射液的临床成果发表于国际顶级学术期刊Nature （Lai et al, Nature, 2026）。此前，相关研究成果已多次获邀在ASH年会上以口头报告及壁报形式向全球血液学界展示。CS-101注射液是全球最早进入临床并且观察期最长的在研碱基编辑管线，其长期安全性与疗效数据持续得到验证。
