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

Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases with potentially life-threatening manifestations. BCL11A is a transcription factor that represses γ-globin expression fetal hemoglobin in erythroid cells. We performed electroporation of CD34+ hematopoietic stem progenitor cells obtained from healthy donors, CRISPR-Cas9 targeting the erythroid-specific enhancer. Approximately 80% alleles at this locus were modified, no evidence off-target editing. After undergoing myeloablation, two patients - one TDT other SCD received autologous edited same More than year later, both had high levels allelic editing bone marrow blood, increases distributed pancellularly, transfusion independence, (in patient SCD) elimination vaso-occlusive episodes. (Funded by CRISPR Therapeutics Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 NCT03745287 SCD-121.).