美国费城宾夕法尼亚大学医学院Stephan A. Grupp课题组研究了exa-cel治疗严重镰状细胞病的疗效与安全性。相关论文发表在2024年4月24日出版的《新英格兰医学杂志》上。

Exagamglogene autotemcel（exa-cel）是一种非病毒细胞疗法，旨在通过体外聚集的规则间隔短回文重复序列（CRISPR）-Cas9基因编辑BCL11A红系特异性增强子区域的自体CD34+造血干细胞和祖细胞（HSPCs），重新激活胎儿血红蛋白合成。

研究组对12至35岁的镰状细胞病患者进行了一项临床3期、单组、开放标签的exa-cel研究，这些患者在筛查前2年中每年至少有两次严重的血管闭塞危象。使用CRISPR-Cas9编辑CD34+HSPCs。在exa-cel输注之前，患者接受了药代动力学剂量调整的白消安的清髓调理。主要终点是至少连续12个月无严重血管闭塞危象。一个关键的次要终点是至少连续12个月免于因严重血管闭塞危机住院治疗。还评估了exa-cel的安全性。

共有44名患者接受了exa-cel，中位随访时间为19.3个月（范围为0.8至48.1）。每个病人体内移植了中性粒细胞和血小板。在有足够随访待评估的30名患者中，29名（97%；95%置信区间[CI]，83~100）至少连续12个月无血管闭塞危象，所有30名（100%；95%可信区间，88至100）患者至少连续12个月没有因血管闭塞性危象住院（与50%缓解的无效假设进行比较，P均<0.001）。exa-cel的安全性与清髓性白消安调理和自体HSPC移植的安全性基本一致。没有发生癌症。

研究结果表明，在97%的镰状细胞病患者中，exa-cel治疗消除了12个月或更长时间的血管闭塞危机。

附：英文原文

Title: Exagamglogene Autotemcel for Severe Sickle Cell Disease

Author: Haydar Frangoul, Franco Locatelli, Akshay Sharma, Monica Bhatia, Markus Mapara, Lyndsay Molinari, Donna Wall, Robert I. Liem, Paul Telfer, Ami J. Shah, Marina Cavazzana, Selim Corbacioglu, Damiano Rondelli, Roland Meisel, Laurence Dedeken, Stephan Lobitz, Mariane de Montalembert, Martin H. Steinberg, Mark C. Walters, Michael J. Eckrich, Suzan Imren, Laura Bower, Christopher Simard, Weiyu Zhou, Fengjuan Xuan, Phuong Khanh Morrow, William E. Hobbs, Stephan A. Grupp

Issue&Volume: 2024-04-24

Abstract:

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.

DOI: NJ202404240000004

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2309676