CRISPR/Cas9-Edited Exa-cel Gene Therapy for Sickle Cell Disease

Exagamglogene autotemcel (exa-cel) is an innovative autologous, ex vivo, CRISPR/Cas9-edited, CD34+ cellular product that induces fetal hemoglobin production by targeting the erythroid enhancer region of BCL11A and ameliorates the severity of sickle cell disease (SCD). In an industry-funded, open-label, phase 3 study, researchers evaluated the efficacy and safety of exa-cel in patients aged 12 to 35 years with SCD and history of at least two severe episodes of vaso-occlusive crises (VOC).

Exa-cel was infused (median dose, 4.0×10⁶ CD34 cells/kg) after myeloablative conditioning with busulfan for 4 days in 44 patients (genotype β^S/β^S in 40, β^S/β⁰ in 3, β^S/β⁺ in 1). Median follow-up was 19.3 months. All patients had successful neutrophil and platelet engraftment. The primary efficacy endpoint — freedom from severe VOC for at least 12 consecutive months — was met by 29 of 30 evaluable patients (97%). Among all patients, the mean percentage of edited BCL11A alleles was 53.5% at 1 month and at least 70% from 2 months on. At 24 months, markers of hemolysis and patient-reported outcomes had improved. Six patients experienced severe VOC after the exa-cel infusion, and compared with patients free from VOC, they had comparable levels of total hemoglobin and fetal hemoglobin and similar percentages of F cells, reticulocyte counts, and allelic editing. The overall toxicity profile was generally consistent with the known risks of autologous stem cell transplantation, myeloablative conditioning by busulfan, and SCD. Long-term follow-up is continuing.