CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia

作者：Haydar Frangoul, David Altshuler, Maria Domenica Cappellini, Yi-Shan Chen, Jennifer Domm, Brenda K. Eustace, Juergen L. Foell, Josu de la Fuente, Stephan A. Grupp, Rupert Handgretinger, Tony W. Ho, Antonis Kattamis, Andrew M. Kernytsky, Julie A. Lekstrom-Himes, Amanda M. Li, Franco Locatelli, Markus Y. Mapara, Mariane de Montalembert, Damiano Rondelli, Akshay Sharma, Sujit Sheth, Sandeep Kumar Soni, Martin H. Steinberg, Donna Ann Wall, Angela Yen, Selim Corbacioglu · 发表于：New England Journal of Medicine · 年份：2020 · DOI：10.1056/nejmoa2031054 · 被引用次数：1973 · 研究领域：Hemoglobinopathies and Related Disorders、Iron Metabolism and Disorders、Parvovirus B19 Infection Studies

Summ a r yTransfusion-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.govnumbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.)T ransfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are the most common monogenic diseases worldwide, with an annual diagnosis in approximately 60,000 patients with TDT and 300,000 patients with SCD.[1][2][3] Both diseases are caused by mutations in the hemoglobin β subunit gene (HBB).Mutations in HBB that cause TDT 4 result in reduced...