From the Sarah Cannon Center for Blood Cancer at the Children's Hospital at TriStar Centennial, Nashville (H.F., J.D.), and St. Jude Children's Research Hospital, Memphis (A.S.) - both in Tennessee; Vertex Pharmaceuticals (D.A., B.K.E., J.L.-H., A.Y.) and Boston University School of Medicine (M.H.S.), Boston, and CRISPR Therapeutics, Cambridge (Y.-S.C., T.W.H., A. Kernytsky, S. Soni) - both in Massachusetts; the University of Milan, Milan (M.D.C.), and Ospedale Pediatrico Bambino Gesù Rome, Sapienza, University of Rome, Rome (F.L.); the University of Regensburg, Regensburg (J. Foell, S.C.), and Children's University Hospital, University of Tübingen, Tübingen (R.H.) - both in Germany; Imperial College Healthcare NHS Trust, St. Mary's Hospital, London (J. de la Fuente); Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (S.G.); the University of Athens, Athens (A. Kattamis); BC Children's Hospital, University of British Columbia, Vancouver (A.M.L.), and the Hospital for Sick Children-University of Toronto, Toronto (D.W.) - both in Canada; Columbia University (M.Y.M.) and the Joan and Sanford I. Weill Medical College of Cornell University (S. Sheth), New York; Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris, Paris (M.M.); and the University of Illinois at Chicago, Chicago (D.R.).
N Engl J Med. 2021 Jan 21;384(3):252-260. doi: 10.1056/NEJMoa2031054. Epub 2020 Dec 5.
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 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 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. (Funded by CRISPR Therapeutics and Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.).
依赖输血的β-地中海贫血症（TDT）和镰状细胞病（SCD）是两种严重的单基因疾病，具有严重且潜在危及生命的表现。BCL11A 是一种转录因子，可抑制红细胞中 γ-珠蛋白的表达和胎儿血红蛋白。我们对来自健康供体的 CD34+造血干细胞和祖细胞进行了电穿孔，使用 CRISPR-Cas9 靶向红细胞特异性增强子。该基因座的大约 80%的等位基因被修饰，没有脱靶编辑的证据。在接受骨髓清除后，两名患者——一名患有 TDT，另一名患有 SCD——接受了靶向相同增强子的 CRISPR-Cas9 编辑的自体 CD34+细胞。一年多后，两名患者的骨髓和血液中均有高水平的等位基因编辑，胎儿血红蛋白分布均匀增加，输血依赖性降低，（在患有 SCD 的患者中）消除了血管阻塞性发作。（由 CRISPR 治疗公司和 Vertex 制药公司资助；临床试验.gov 编号，CLIMB THAL-111 为 NCT03655678，CLIMB SCD-121 为 NCT03745287）。
