Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia (CHOP), Philadelphia, PA, USA.
Laboratory of chromatin and gene regulation during development, INSERM UMR1163, Paris, France.
Hum Mol Genet. 2019 Oct 1;28(R1):R24-R30. doi: 10.1093/hmg/ddz172.
Recently, gene therapy clinical trials have been successfully applied to hemoglobinopathies, such as sickle cell disease (SCD) and β-thalassemia. Among the great discoveries that led to the design of genetic approaches to cure these disorders is the discovery of the β-globin locus control region and several associated transcription factors, which determine hemoglobin switching as well as high-level, erythroid-specific expression of genes at the ß-globin locus. Moreover, increasing evidence shows that lentiviral vectors are efficient tools to insert large DNA elements into nondividing hematopoietic stem cells, showing reassuring safe integration profiles. Alternatively, genome editing could restore expression of fetal hemoglobin or target specific mutations to restore expression of the wild-type β-globin gene. The most recent clinical trials for β-thalassemia and SCD are showing promising outcomes: patients were able to discontinue transfusions or had reduced transfusion requirements. However, toxic myeloablation and the high cost of current ex vivo hematopoietic stem cell gene therapy platforms represent a barrier to a widespread application of these approaches. In this review, we summarize these gene therapy strategies and ongoing clinical trials. Finally, we discuss possible strategies to improve outcomes, reduce myeloablative regimens and future challenges to reduce the cost of gene therapy platform.
最近，基因治疗临床试验已成功应用于血红蛋白病，如镰状细胞病（SCD）和β-地中海贫血。在导致设计基因方法治疗这些疾病的重大发现中，有β-珠蛋白基因座控制区和几个相关转录因子的发现，这些发现决定了血红蛋白的转换以及β-珠蛋白基因座上基因的高水平、红系特异性表达。此外，越来越多的证据表明，慢病毒载体是将大的 DNA 元件插入非分裂造血干细胞的有效工具，具有令人放心的安全整合特征。或者，基因组编辑可以恢复胎儿血红蛋白的表达，或针对特定突变以恢复野生型β-珠蛋白基因的表达。针对β-地中海贫血和 SCD 的最新临床试验显示出有希望的结果：患者能够停止输血或减少输血需求。然而，细胞毒性骨髓清除和当前体外造血干细胞基因治疗平台的高成本是这些方法广泛应用的障碍。在这篇综述中，我们总结了这些基因治疗策略和正在进行的临床试验。最后，我们讨论了改善结果、减少骨髓清除方案和降低基因治疗平台成本的未来挑战的可能策略。
