美国TriStar Centennial儿童医院Haydar Frangoul联合德国雷根斯堡大学Selim Corbacioglu团队，研究了CRISPR-Cas9基因编辑治疗镰状细胞病和β-地中海贫血的疗效。2020年12月5日，该研究发表在《新英格兰医学杂志》上。

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，症状严重时可能危及生命。BCL11A是一种转录因子，可抑制红系细胞中的γ-珠蛋白表达和胎儿血红蛋白。

研究组对从健康供体获得的CD34+造血干祖细胞进行电穿孔，使用CRISPR-Cas9靶向BCL11A红系特异性增强子。大约80%的等位基因在这个基因座上被修改，没有脱靶编辑的迹象。进行骨髓消融后，两名患者（一名患有TDT，另一名患有SCD）接受了CRISPR-Cas9编辑的针对同一BCL11A增强子的自体CD34 +细胞。

一年多以后，两名患者的骨髓和血液中的等位基因编辑水平较高，全细胞分布的胎儿血红蛋白增加，不再依赖输血，其中SCD患者还消除了血管闭塞性发作。

附：英文原文

Title: CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia | NEJM

Author: Haydar Frangoul, M.D.,, David Altshuler, M.D., Ph.D.,, M. Domenica Cappellini, M.D.,, Yi-Shan Chen, Ph.D.,, Jennifer Domm, M.D.,, Brenda K. Eustace, Ph.D.,, Juergen Foell, M.D.,, Josu de la Fuente, M.D., Ph.D.,, Stephan Grupp, M.D., Ph.D.,, Rupert Handgretinger, M.D.,, Tony W. Ho, M.D.,, Antonis Kattamis, M.D.,, Andrew Kernytsky, Ph.D.,, Julie Lekstrom-Himes, M.D.,, Amanda M. Li, M.D.,, Franco Locatelli, M.D.,, Markus Y. Mapara, M.D., Ph.D.,, Mariane de Montalembert, M.D.,, Damiano Rondelli, M.D.,, Akshay Sharma, M.B., B.S.,, Sujit Sheth, M.D.,, Sandeep Soni, M.D.,, Martin H. Steinberg, M.D.,, Donna Wall, M.D.,, Angela Yen, Ph.D.,, and Selim Corbacioglu, M.D.

Issue&Volume: 2020-12-05

Abstract: Transfusion-dependent β-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 γ-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.

DOI: 10.1056/NEJMoa2031054

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2031054