Zarghamian Parinaz, Klermund Julia, Cathomen Toni
Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg, Freiburg, Germany.
Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Front Med (Lausanne). 2023 Jan 9;9:1065377. doi: 10.3389/fmed.2022.1065377. eCollection 2022.
Sickle cell disease (SCD) is one of the most common hemoglobinopathies. Due to its high prevalence, with about 20 million affected individuals worldwide, the development of novel effective treatments is highly warranted. While transplantation of allogeneic hematopoietic stem cells (HSC) is the standard curative treatment approach, a variety of gene transfer and genome editing strategies have demonstrated their potential to provide a prospective cure for SCD patients. Several stratagems employing CRISPR-Cas nucleases or base editors aim at reactivation of γ-globin expression to replace the faulty β-globin chain. The fetal hemoglobin (HbF), consisting of two α-globin and two γ-globin chains, can compensate for defective adult hemoglobin (HbA) and reverse the sickling of hemoglobin-S (HbS). Both disruption of -regulatory elements that are involved in inhibiting γ-globin expression, such as BCL11A or LRF binding sites in the γ-globin gene promoters (), or the lineage-specific disruption of BCL11A to reduce its expression in human erythroblasts, have been demonstrated to reestablish HbF expression. Alternatively, the point mutation in the gene has been corrected using homology-directed repair (HDR)-based methodologies. In general, genome editing has shown promising results not only in preclinical animal models but also in clinical trials, both in terms of efficacy and safety. This review provides a brief update on the recent clinical advances in the genome editing space to offer cure for SCD patients, discusses open questions with regard to off-target effects induced by the employed genome editors, and gives an outlook of forthcoming developments.
镰状细胞病（SCD）是最常见的血红蛋白病之一。由于其高患病率，全球约有2000万人受影响，因此非常有必要开发新的有效治疗方法。虽然异基因造血干细胞（HSC）移植是标准的治愈性治疗方法，但多种基因转移和基因组编辑策略已证明它们有潜力为SCD患者提供前瞻性治愈方案。几种采用CRISPR-Cas核酸酶或碱基编辑器的策略旨在重新激活γ-珠蛋白表达以替代有缺陷的β-珠蛋白链。由两条α-珠蛋白链和两条γ-珠蛋白链组成的胎儿血红蛋白（HbF）可以补偿有缺陷的成人血红蛋白（HbA）并逆转血红蛋白S（HbS）的镰变。破坏参与抑制γ-珠蛋白表达的调控元件，如γ-珠蛋白基因启动子中的BCL11A或LRF结合位点，或在人类成红细胞中对BCL11A进行谱系特异性破坏以降低其表达，均已证明可重新建立HbF表达。另外，已使用基于同源定向修复（HDR）的方法纠正了基因中的点突变。总体而言，基因组编辑不仅在临床前动物模型中，而且在临床试验中，在疗效和安全性方面都显示出了有前景的结果。本综述简要介绍了基因组编辑领域最近在为SCD患者提供治愈方案方面的临床进展，讨论了所采用的基因组编辑器诱导的脱靶效应相关的未解决问题，并展望了即将到来的发展。
