Dana Farber/Boston Children's Cancer and Blood Disorders Center, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA; email:
Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA; email:
Annu Rev Med. 2019 Jan 27;70:257-271. doi: 10.1146/annurev-med-041817-125507. Epub 2018 Oct 24.
The genetic basis of sickle cell disease (SCD) was elucidated >60 years ago, yet current therapy does not rely on this knowledge. Recent advances raise prospects for improved, and perhaps curative, treatment. First, transcription factors, BCL11A and LRF/ZBTB7A, that mediate silencing of the β-like fetal (γ-) globin gene after birth have been identified and demonstrated to act at the γ-globin promoters, precisely at recognition sequences disrupted in rare individuals with hereditary persistence of fetal hemoglobin. Second, transformative advances in gene editing and progress in lentiviral gene therapy provide diverse opportunities for genetic strategies to cure SCD. Approaches include hematopoietic gene therapy by globin gene addition, gene editing to correct the SCD mutation, and genetic manipulations to enhance fetal hemoglobin production, a potent modifier of the clinical phenotype. Clinical trials may soon identify efficacious and safe genetic approaches to the ultimate goal of cure for SCD.
镰状细胞病（SCD）的遗传基础在 60 多年前就已阐明，但目前的治疗方法并不依赖于此。最近的进展为改善治疗方法，甚至可能实现治愈，带来了希望。首先，已经鉴定出转录因子 BCL11A 和 LRF/ZBTB7A，它们介导出生后β样胎儿（γ-）珠蛋白基因的沉默，并已证明其在γ珠蛋白启动子上发挥作用，而这些启动子在具有遗传性胎儿血红蛋白持续存在的罕见个体中被破坏。其次，基因编辑的革命性进展和慢病毒基因治疗的进展为治疗 SCD 的基因策略提供了多样化的机会。方法包括通过珠蛋白基因添加进行造血基因治疗、纠正 SCD 突变的基因编辑以及增强胎儿血红蛋白产生的基因操作，这是临床表型的有力修饰因子。临床试验可能很快就会确定有效和安全的基因方法，以实现 SCD 的最终治愈目标。
