@article{uoadl:3492165,
    volume = "390",
    number = "18",
    pages = "1663 – 1676",
    journal = "The New England journal of medicine",
    keywords = "Adolescent; Adult; Antigens, CD34; beta-Thalassemia; Blood Transfusion; Busulfan; Child; CRISPR-Cas Systems; Female; Fetal Hemoglobin; Gene Editing; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Male; Repressor Proteins; Transplantation Conditioning; Transplantation, Autologous; Young Adult; busulfan; CD34 antigen; exagamglogene autotemcel; ferritin; granulocyte colony stimulating factor; messenger RNA; BCL11A protein, human; busulfan; CD34 antigen; hemoglobin F; repressor protein; adolescent; adult; anemia; Article; assessment of humans; BCL11A gene; beta thalassemia; Bone   Marrow Transplantation Subscale; child; clinical trial; clustered regularly interspaced short palindromic repeat; CRISPR-CAS9 system; drug efficacy; drug safety; electrocardiogram; epistaxis; EuroQol Visual Analogue Scale; febrile neutropenia; female; follow up; Functional Assessment of  Cancer  Therapy–General; gene; gene editing; genetic modification; genotype; headache; hematopoietic stem cell; hematuria; hemoglobin blood level; human; hypokalemia; hypophosphatemia; hypoxia; major clinical study; male; mortality; nausea; neutropenia; patient-reported outcome; physical examination; platelet count; stomatitis; thrombocyte transfusion; thrombocytopenia; transfusion; vomiting; autotransplantation; beta thalassemia; blood transfusion; CRISPR Cas system; gene editing; genetics; hematopoietic stem cell transplantation; multicenter study; phase 3 clinical trial; transplantation conditioning; young adult",
    BIBTEX_ENTRY = "article",
    year = "2024",
    author = "Locatelli, F. and Lang, P. and Wall, D. and Meisel, R. and Corbacioglu, S. and Li, A.M. and De La Fuente, J. and Shah, A.J. and Carpenter, B. and Kwiatkowski, J.L. and Mapara, M. and Liem, R.I. and Cappellini, M.D. and Algeri, M. and Kattamis, A. and Sheth, S. and Grupp, S. and Handgretinger, R. and Kohli, P. and Shi, D. and Ross, L. and Bobruff, Y. and Simard, C. and Zhang, L. and Morrow, P.K. and Hobbs, W.E. and Frangoul, H.",
    abstract = "BACKGROUND Exagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis through ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing of the erythroid-specific enhancer region of BCL11A in autologous CD34+ hematopoietic stem and progenitor cells (HSPCs). METHODS We conducted an open-label, single-group, phase 3 study of exa-cel in patients 12 to 35 years of age with transfusion-dependent β-thalassemia and a β0/β0, β0/β0-like, or non-β0/β0-like genotype. CD34+ HSPCs were edited by means of CRISPR-Cas9 with a guide mRNA. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was transfusion independence, defined as a weighted average hemoglobin level of 9 g per deciliter or higher without red-cell transfusion for at least 12 consecutive months. Total and fetal hemoglobin concentrations and safety were also assessed. RESULTS A total of 52 patients with transfusion-dependent β-thalassemia received exa-cel and were included in this prespecified interim analysis; the median follow-up was 20.4 months (range, 2.1 to 48.1). Neutrophils and platelets engrafted in each patient. Among the 35 patients with sufficient follow-up data for evaluation, transfusion independence occurred in 32 (91%; 95% confidence interval, 77 to 98; P<0.001 against the null hypothesis of a 50% response). During transfusion independence, the mean total hemoglobin level was 13.1 g per deciliter and the mean fetal hemoglobin level was 11.9 g per deciliter, and fetal hemoglobin had a pancellular distribution (≥94% of red cells). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No deaths or cancers occurred. CONCLUSIONS Treatment with exa-cel, preceded by myeloablation, resulted in transfusion independence in 91% of patients with transfusion-dependent β-thalassemia. (Supported by Vertex Pharmaceuticals and CRISPR Therapeutics; CLIMB THAL-111 ClinicalTrials.gov number, NCT03655678.). © 2024 Massachussetts Medical Society. All rights reserved.",
    title = "Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia",
    doi = "10.1056/NEJMOA2309673"
}