The New England journal of medicine · 2020
CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia.
Клиническое исследованиеСтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Frangoul Haydar, Altshuler David, Cappellini M Domenica, Chen Yi-Shan, Domm Jennifer, Eustace Brenda K, Foell Juergen, de la Fuente Josu, Grupp Stephan, Handgretinger Rupert, Ho Tony W, Kattamis Antonis, Kernytsky Andrew, Lekstrom-Himes Julie, Li Amanda M, Locatelli Franco, Mapara Markus Y, de Montalembert Mariane, Rondelli Damiano, Sharma Akshay, Sheth Sujit, Soni Sandeep, Steinberg Martin H, Wall Donna, Yen Angela, Corbacioglu Selim
Аннотация
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. (Funded by CRISPR Therapeutics and Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.).