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

TLDR

Transfusion‑dependent β‑thalassemia and sickle cell disease are severe monogenic disorders, and the transcription factor BCL11A suppresses fetal hemoglobin in erythroid cells. The study used CRISPR‑Cas9 to electroporate CD34+ hematopoietic stem cells from healthy donors targeting the BCL11A erythroid enhancer, then transplanted the edited cells into two patients after myeloablation. Approximately 80 % of BCL11A alleles were edited with no off‑target effects, and more than a year later both patients exhibited high marrow and blood editing, pancellular fetal hemoglobin elevation, transfusion independence, and in the SCD patient complete resolution of vaso‑occlusive crises. The work was funded by CRISPR Therapeutics and Vertex Pharmaceuticals and registered under ClinicalTrials.gov NCT03655678 (CLIMB THAL‑111) and NCT03745287 (CLIMB SCD‑121).

Abstract

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.).