Haematology Unit, Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Serdang, Selangor, Malaysia.
Genetics and Regenerative Medicine Research Centre, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Serdang, Selangor, Malaysia.
Cardiovasc Hematol Disord Drug Targets. 2023;22(4):226-236. doi: 10.2174/1871529X23666230123140926.
β-thalassaemia is a genetic disorder resulting in a reduction or absence of β-globin gene expression. Due to the high prevalence of β-thalassaemia and the lack of available treatment other than blood transfusion and haematopoietic stem cell (HSC) transplantation, the disease represents a considerable burden to clinical and economic systems. Foetal haemoglobin has an appreciated ameliorating effect in β-haemoglobinopathy, as the γ-globin chain substitutes the β-globin chain reduction by pairing with the excess α-globin chain in β-thalassaemia and reduces sickling in sickle cell disease (SCD). BCL11A is a critical regulator and repressor of foetal haemoglobin. Downregulation of BCL11A in adult erythroblasts and cell lines expressing adult haemoglobin led to a significant increase in foetal haemoglobin levels. Disruption of BCL11A erythroid enhancer resulted in disruption of the BCL11A gene solely in the erythroid lineages and increased γ-globin expression in adult erythroid cells. Autologous haematopoietic stem cell gene therapy represents an attractive treatment option to overcome the immune complications and donor availability associated with allogeneic transplantation. Using genome editing technologies, the disruption of BCL11A to induce γ- globin expression in HSCs has emerged as an alternative approach to treat β-thalassaemia. Targeting the +58 BCL11A erythroid enhancer or BCL11A binding motif at the γ-gene promoter with CRISPR-Cas9 or base editors has successfully disrupted the gene and the binding motif with a subsequent increment in HbF levels. This review outlines the critical role of BCL11A in γ-globin gene silencing and discusses the different genome editing approaches to downregulate BCL11A as a means for ameliorating β-thalassaemia.
β-地中海贫血是一种遗传性疾病，导致β-珠蛋白基因表达减少或缺失。由于β-地中海贫血的高患病率以及除输血和造血干细胞 (HSC) 移植之外缺乏可用的治疗方法，该疾病对临床和经济系统构成了相当大的负担。胎儿血红蛋白在β-血红蛋白病中有明显的改善作用，因为γ-珠蛋白链通过与β-地中海贫血中过量的α-珠蛋白链配对来替代β-珠蛋白链的减少，并减少镰状细胞病 (SCD) 中的镰状化。BCL11A 是胎儿血红蛋白的关键调节因子和抑制剂。在表达成人血红蛋白的成人红细胞和成纤维细胞系中下调 BCL11A 导致胎儿血红蛋白水平显著增加。BCL11A 红细胞增强子的破坏导致仅在红细胞谱系中破坏 BCL11A 基因，并增加成人红细胞中的γ-珠蛋白表达。自体造血干细胞基因治疗是克服与同种异体移植相关的免疫并发症和供体可用性的有吸引力的治疗选择。使用基因组编辑技术，破坏 BCL11A 以诱导 HSCs 中的 γ-珠蛋白表达已成为治疗β-地中海贫血的替代方法。使用 CRISPR-Cas9 或碱基编辑器靶向 +58 BCL11A 红细胞增强子或 γ-基因启动子上的 BCL11A 结合基序已成功破坏基因和结合基序，随后 HbF 水平增加。这篇综述概述了 BCL11A 在 γ-珠蛋白基因沉默中的关键作用，并讨论了不同的基因组编辑方法来下调 BCL11A 作为改善β-地中海贫血的一种手段。
