Gene editing to disrupt the GATA1-binding site at the +58 BCL11A erythroid enhancer could induce γ-globin expression, which is a promising therapeutic strategy to alleviate β-hemoglobinopathy caused by HBB gene mutation. In the present study, we report the preliminary results of an ongoing phase 1/2 trial (NCT04211480) evaluating safety and efficacy of gene editing therapy in children with blood transfusion-dependent β-thalassemia (TDT). We transplanted BCL11A enhancer-edited, autologous, hematopoietic stem and progenitor cells into two children, one carrying the β⁰/β⁰ genotype, classified as the most severe type of TDT. Primary endpoints included engraftment, overall survival and incidence of adverse events (AEs). Both patients were clinically well with multilineage engraftment, and all AEs to date were considered unrelated to gene editing and resolved after treatment. Secondary endpoints included achieving transfusion independence, editing rate in bone marrow cells and change in hemoglobin (Hb) concentration. Both patients achieved transfusion independence for >18 months after treatment, and their Hb increased from 8.2 and 10.8 g dl⁻¹ at screening to 15.0 and 14.0 g dl⁻¹ at the last visit, respectively, with 85.46% and 89.48% editing persistence in bone marrow cells. Exploratory analysis of single-cell transcriptome and indel patterns in edited peripheral blood mononuclear cells showed no notable side effects of the therapy.

基因编辑破坏+58 BCL11A红系增强子的GATA1结合位点可诱导γ-珠蛋白表达，这是缓解HBB基因突变引起的β-血红蛋白病的有前景的治疗策略。在本研究中，我们报告了一项正在进行的 1/2 期试验 (NCT04211480) 的初步结果，该试验评估了输血依赖性 β-地中海贫血 (TDT) 儿童基因编辑治疗的安全性和有效性。我们将BCL11A增强子编辑的自体造血干细胞和祖细胞移植到两个孩子身上，一个携带 β ⁰ /β ⁰基因型，分类为最严重的 TDT 类型。主要终点包括植入、总生存期和不良事件 (AE) 的发生率。两名患者的多系移植临床表现良好，迄今为止所有 AE 均被认为与基因编辑无关，并在治疗后得到解决。次要终点包括实现输血独立性、骨髓细胞的编辑率和血红蛋白 (Hb) 浓度的变化。两名患者在治疗后超过 18 个月实现了不依赖输血，并且他们的 Hb 从筛选时的 8.2 和 10.8 g dl ^-1增加到 15.0 和 14.0 g dl ^-1在最后一次访问中，分别有 85.46% 和 89.48% 的编辑持续存在于骨髓细胞中。对编辑的外周血单核细胞中单细胞转录组和插入缺失模式的探索性分析显示该疗法没有明显的副作用。