CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia
CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia
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DOI：
10.1056/nejmoa2031054
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发表时间：
2021-01-21
影响因子：
158.5
通讯作者：
Corbacioglu, S.
中科院分区：
文献类型：
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作者：
Frangoul, H.;Altshuler, D.;Corbacioglu, S.
输血依赖性β-地中海贫血（TDT）和镰状细胞病（SCD）是严重的单基因疾病，具有严重和潜在的危及生命的表现。BCL 11 A是一种转录因子，抑制红系细胞中的γ-珠蛋白表达和胎儿血红蛋白。我们对从健康供体获得的CD 34+造血干细胞和祖细胞进行电穿孔，其中CRISPR-Cas9靶向BCL 11 A红细胞特异性增强子。该基因座上大约80%的等位基因被修饰，没有脱靶编辑的证据。在接受骨髓消融术后，两名患者-一名患有TDT，另一名患有SCD -接受了用CRISPR-Cas9编辑的自体CD 34+细胞，靶向相同的BCL 11 A增强子。一年多后，这两名患者的骨髓和血液中都有高水平的等位基因编辑，胎儿血红蛋白增加，分布在全细胞内，不依赖输血，并且（在SCD患者中）消除了血管闭塞发作。
Transfusion-dependent beta-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases with severe and potentially life-threatening manifestations. BCL11A is a transcription factor that represses gamma-globin expression and fetal hemoglobin in erythroid cells. We performed electroporation of CD34+ hematopoietic stem and progenitor cells obtained from healthy donors, with CRISPR-Cas9 targeting the BCL11A erythroid-specific enhancer. Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same BCL11A enhancer. More than a year later, both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes.