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期刊来源：N Engl J Med

原文链接：https://doi.org/10.1056/NEJMoa2309676

摘要内容如下：

背景

Exagamglogene Autotemcel（Exa-Cel）是一种非病毒细胞疗法，旨在通过在BCL11A的红系特异性增强子区对自体CD34+造血干细胞和祖细胞（HSPCs）进行体外成簇的规则间隔短回文重复序列（CRISPR）-Cas9基因编辑来重新激活胎儿血红蛋白合成。

方法

我们在12至35岁的镰状细胞病患者中进行了一项3期、单组、开放标签的Exa-Cel研究，这些患者在筛查前2年内每年至少发生2次严重的血管闭塞危象。使用CRISPR-Cas9编辑CD34+HSPCs。在输注Exa-Cel之前，患者接受了药代动力学剂量调整的白消安的清髓性预处理。主要终点是至少连续12个月未出现严重的血管闭塞危象。关键的次要终点是至少连续12个月未因严重血管闭塞危象而住院。此外，还评估了Exa-Cel的安全性。

结果

共有44名患者接受了Exa-Cel治疗，中位随访时间为19.3个月（0.8至48.1个月）。中性粒细胞和血小板在每个患者中植入。在有足够随访的30例患者中，29例（97%；95%可信区间[CI]，83-100）至少连续12个月无血管闭塞危象，所有30例（100%；95%CI，88至100）至少连续12个月未因血管闭塞危象住院（与50%缓解的零假设相比，两项比较均P<0.001）。Exa-Cel的安全性与清髓性白消安预处理和自体HSPC移植的安全性基本一致。未发生癌症。

结论

在12个月或更长的时间内，Exa-Cel治疗消除了97%的镰状细胞病患者的血管闭塞危象。（Climb SCD-121；ClinicalTrials.gov编号，NCT03745287。）

英文原文如下：

Abstracts

BACKGROUND  Exagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis by means of ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) at the erythroid-specific enhancer region of BCL11A.

METHODS  We conducted a phase 3, single-group, open-label study of exa-cel in patients 12 to 35 years of age with sickle cell disease who had had at least two severe vaso-occlusive crises in each of the 2 years before screening. CD34+ HSPCs were edited with the use of CRISPR-Cas9. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was freedom from severe vaso-occlusive crises for at least 12 consecutive months. A key secondary end point was freedom from inpatient hospitalization for severe vaso-occlusive crises for at least 12 consecutive months. The safety of exa-cel was also assessed.

RESULTS  A total of 44 patients received exa-cel, and the median follow-up was 19.3 months (range, 0.8 to 48.1). Neutrophils and platelets engrafted in each patient. Of the 30 patients who had sufficient follow-up to be evaluated, 29 (97%; 95% confidence interval [CI], 83 to 100) were free from vaso-occlusive crises for at least 12 consecutive months, and all 30 (100%; 95% CI, 88 to 100) were free from hospitalizations for vaso-occlusive crises for at least 12 consecutive months (P<0.001 for both comparisons against the null hypothesis of a 50% response). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No cancers occurred.

CONCLUSIONS  Treatment with exa-cel eliminated vaso-occlusive crises in 97% of patients with sickle cell disease for a period of 12 months or more. (CLIMB SCD-121; ClinicalTrials.gov number, NCT03745287.).

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