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

AbstractTransfusion-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. (Funded by CRISPR Therapeutics and Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.).Copyright © 2020 Massachusetts Medical Society.

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