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期刊来源：N Engl J Med

原文链接：https://doi.org/10.1056/NEJMoa2309673

摘要内容如下：

背景

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

方法

我们在12至35岁的输血依赖性β-地中海贫血患者（β0/β0、β0/β0样或非β0/β0样基因型）中进行了一项开放标签、单组、3期Exa-Cel研究。通过CRISPR-Cas9和引导mRNA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。主要终点是输血独立性，定义为至少连续12个月未输注红细胞的加权平均血红蛋白水平为每分升9克或更高。还评估了总血红蛋白浓度和胎儿血红蛋白浓度以及安全性。

结果

共有52例输血依赖型β-地中海贫血患者接受了Exa-Cel治疗，并纳入了这一预先指定的中期分析。中位随访时间为20.4个月（2.1~48.1个月）。中性粒细胞和血小板在每个患者中植入。在35例有足够随访资料可供评估的患者中，32例（91%；95%置信区间，77至98；相对于50%响应的零假设，P<0.001）。在独立输血期间，平均总血红蛋白水平为13.1 G/DL，平均胎儿血红蛋白水平为11.9 G/DL，胎儿血红蛋白呈全细胞分布（≥94%的红细胞）。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。没有死亡或癌症发生。

结论

91%的输血依赖性β-地中海贫血患者在接受骨髓消融术前接受Exa-Cel治疗，可不依赖输血。（由Vertex Pharmaceuticals和CRISPR Therapeutics提供支持；Climb Thal-111 ClinicalTrials.gov编号，NCT03655678。）

英文原文如下：

Abstracts

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

METHODS  We conducted an open-label, single-group, phase 3 study of exa-cel in patients 12 to 35 years of age with transfusion-dependent β-thalassemia and a β0/β0, β0/β0-like, or non-β0/β0-like genotype. CD34+ HSPCs were edited by means of CRISPR-Cas9 with a guide mRNA. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was transfusion independence, defined as a weighted average hemoglobin level of 9 g per deciliter or higher without red-cell transfusion for at least 12 consecutive months. Total and fetal hemoglobin concentrations and safety were also assessed.

RESULTS  A total of 52 patients with transfusion-dependent β-thalassemia received exa-cel and were included in this prespecified interim analysis; the median follow-up was 20.4 months (range, 2.1 to 48.1). Neutrophils and platelets engrafted in each patient. Among the 35 patients with sufficient follow-up data for evaluation, transfusion independence occurred in 32 (91%; 95% confidence interval, 77 to 98; P<0.001 against the null hypothesis of a 50% response). During transfusion independence, the mean total hemoglobin level was 13.1 g per deciliter and the mean fetal hemoglobin level was 11.9 g per deciliter, and fetal hemoglobin had a pancellular distribution (≥94% of red cells). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No deaths or cancers occurred.

CONCLUSIONS  Treatment with exa-cel, preceded by myeloablation, resulted in transfusion independence in 91% of patients with transfusion-dependent β-thalassemia. (Supported by Vertex Pharmaceuticals and CRISPR Therapeutics; CLIMB THAL-111 ClinicalTrials.gov number, NCT03655678.).

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