上海华东师范大学Yuxuan Wu，Mingyao Liu，Dali Li和湖南中南大学湘雅医院Bin Fu共同合作近期取得重要工作进展，他们研究利用CRISPR-Cas9介导的BCL11A增强子的基因编辑治疗小儿β0/β0输血依赖性β地中海贫血症。这一研究成果2022年8月4日在线发表于《自然—医学》杂志上。

在本研究中，研究人员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。研究人员将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β0/β0基因型，被归类为最严重的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AEs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个月实现了输血独立，他们的Hb从筛选时的8.2和 10.8 g dl^-1分别增加到最后一次访问时的15.0和14.0 g dl^-1，其中85.46%和89.48%的编辑持续性在骨髓细胞。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。

据介绍，通过基因编辑破坏+58 BCL11A红细胞增强子上的GATA1结合位点，可诱导γ-珠蛋白表达，是缓解HBB基因突变导致的β-血红蛋白病的一种有前景的治疗策略。

附：英文原文

Title: CRISPR–Cas9-mediated gene editing of the BCL11A enhancer for pediatric β0/β0 transfusion-dependent β-thalassemia

Author: Fu, Bin, Liao, Jiaoyang, Chen, Shuanghong, Li, Wei, Wang, Qiudao, Hu, Jian, Yang, Fei, Hsiao, Shenlin, Jiang, Yanhong, Wang, Liren, Chen, Fangping, Zhang, Yuanjin, Wang, Xin, Li, Dali, Liu, Mingyao, Wu, Yuxuan

Issue&Volume: 2022-08-04

Abstract: 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 >18months after treatment, and their Hb increased from 8.2 and 10.8gdl1 at screening to 15.0 and 14.0gdl1 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.

DOI: 10.1038/s41591-022-01906-z

Source: https://www.nature.com/articles/s41591-022-01906-z