Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institutes, National Institutes of Health, Bethesda, MD, USA.
Hum Mol Genet. 2020 Sep 30;29(R1):R100-R106. doi: 10.1093/hmg/ddaa088.
Genome editing to correct a defective β-globin gene or induce fetal globin (HbF) for patients with beta-hemoglobinopathies has the potential to be a curative strategy available to all. HbF reactivation has long been an area of intense interest given the HbF inhibition of sickle hemoglobin (HbS) polymerization. Patients with HbS who also have high HbF tend to have less severe or even minimal clinical manifestations. Approaches to genetically engineer high HbF include de novo generation of naturally occurring hereditary persistence of fetal hemoglobin (HPFH) mutations, editing of transcriptional HbF repressors or their binding sites and/or regulating epigenetic intermediates controlling HbF expression. Recent preclinical and early clinical trial data show encouraging results; however, long-term follow-up is lacking, and the safety and efficacy concerns of genome editing remain.
基因组编辑纠正缺陷的β-珠蛋白基因或诱导胎儿血红蛋白（HbF）用于β-地中海贫血患者有可能成为一种普遍适用的治疗策略。由于 HbF 抑制镰状血红蛋白（HbS）聚合，HbF 的重新激活一直是一个研究热点。具有高 HbF 的 HbS 患者往往症状较轻，甚至没有明显的临床表现。提高 HbF 的基因工程方法包括新生成天然存在的遗传性胎儿血红蛋白持续存在（HPFH）突变、编辑转录 HbF 抑制剂或其结合位点和/或调节控制 HbF 表达的表观遗传中间产物。最近的临床前和早期临床试验数据显示出令人鼓舞的结果；然而，缺乏长期随访，基因组编辑的安全性和有效性问题仍然存在。
