依泊汀α 基因修饰自体造血干/祖细胞治疗输血依赖型β 地中海贫血

Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia.

机构信息

From IRCCS Ospedale Pediatrico Bambino Gesù (F.L., M.A.) and Catholic University of the Sacred Heart (F.L.), Rome, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan (M.D.C.), and the Department of Health Sciences, Magna Graecia University, Catanzaro (M.A.) - all in Italy; University Children's Hospital Tübingen (R.H.), and the Cluster of Excellence iFIT (EXC 2180) "Image-guided and Functionally Instructed Tumor Therapies" and the German Cancer Consortium, Partner Site Tübingen, University of Tübingen (P.L.), Tübingen, the Division of Pediatric Stem Cell Therapy, Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf (R.M.), and the University of Regensburg, Regensburg (S.C.) - all in Germany; the Hospital for Sick Children and University of Toronto, Toronto (D.W.), and BC Children's Hospital, University of British Columbia, Vancouver (A.M.L.) - all in Canada; Imperial College Healthcare NHS Trust, St. Mary's Hospital (J.F.), and University College London Hospitals NHS Foundation Trust (B.C.) - both in London; Stanford University, Palo Alto, CA (A.J.S.); Children's Hospital of Philadelphia and Perlman School of Medicine, University of Pennsylvania, Philadelphia (J.L.K., S.G.); Herbert Irving Comprehensive Cancer Center, Columbia University (M.M.), and Joan and Sanford I. Weill Medical College of Cornell University (S.S.) - both in New York; Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago (R.I.L.); National and Kapodistrian University of Athens, Athens (A.K.); Vertex Pharmaceuticals, Boston (P.K., D.S., L.R., Y.B., C.S., L.Z., W.E.H.), and CRISPR Therapeutics, Cambridge (P.K.M.) - both in Massachusetts; and Sarah Cannon Research Institute at the Children's Hospital at TriStar Centennial, Nashville (H.F.).

出版信息

N Engl J Med. 2024 May 9;390(18):1663-1676. doi: 10.1056/NEJMoa2309673. Epub 2024 Apr 24.

DOI:10.1056/NEJMoa2309673

PMID:38657265

Abstract

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 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 β/β, β/β-like, or non-β/β-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.).

摘要

背景

Exagamglogene autotemcel（exa-cel）是一种非病毒细胞疗法，旨在通过体外 CRISPR-Cas9 基因编辑靶向β珠蛋白基因的红细胞特异性增强子区域，重新激活胎儿血红蛋白的合成。该疗法使用的是自体 CD34+造血干细胞和祖细胞（HSPCs）。

方法

我们开展了一项开放标签、单组、3 期临床试验，纳入了年龄在 12 岁至 35 岁、依赖输血的β地中海贫血患者，患者的基因型为β/β、β/β 样或非β/β 样。通过 CRISPR-Cas9 与指导 mRNA 对 CD34+HSPC 进行编辑。在 exa-cel 输注前，患者接受了药代动力学剂量调整的白消安骨髓清除预处理。主要终点是输血独立性，定义为血红蛋白平均水平达到 9g/dL 或更高，且至少连续 12 个月无需输注红细胞。还评估了总血红蛋白和胎儿血红蛋白浓度以及安全性。

结果

共有 52 名依赖输血的β地中海贫血患者接受了 exa-cel 治疗，并纳入本研究预先设定的中期分析；中位随访时间为 20.4 个月（范围，2.1 至 48.1）。每位患者的中性粒细胞和血小板均成功植入。在 35 名有足够随访数据进行评估的患者中，32 名（91%；95%置信区间，77 至 98；与 50%应答率的零假设相比，P<0.001）达到输血独立性。在输血独立性期间，平均总血红蛋白水平为 13.1g/dL，平均胎儿血红蛋白水平为 11.9g/dL，且胎儿血红蛋白具有全细胞分布（≥94%的红细胞）。exa-cel 的安全性与骨髓清除白消安预处理和自体 HSPC 移植一致。未发生死亡或癌症。

结论

在依赖输血的β地中海贫血患者中，exa-cel 治疗（ preceded by myeloablation）使 91%的患者达到输血独立性。（由 Vertex 制药公司和 CRISPR 治疗公司资助；CLIMB THAL-111 ClinicalTrials.gov 编号，NCT03655678。）