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β-hemoglobinopathies are caused by abnormal or absent production of hemoglobin in the blood due to mutations in the  β-globin  gene ( HBB ). Imbalanced expression of adult hemoglobin (HbA) induces strong anemia in patients suffering from the disease. However, individuals with natural-occurring mutations in the  HBB  cluster or related genes, compensate this disparity through  γ-globin  expression and subsequent fetal hemoglobin (HbF) production. Several preclinical and clinical studies have been performed in order to induce HbF by knocking-down genes involved in HbF repression ( KLF1  and  BCL11A ) or disrupting the binding sites of several transcription factors in the  γ-globin  gene ( HBG1/2 ). In this study, we thoroughly compared the different CRISPR/Cas9 gene-disruption strategies by gene editing analysis and assessed their safety profile by RNA-seq and GUIDE-seq. All approaches reached therapeutic levels of HbF after gene editing and showed similar gene expression to the control sample, while no significant off-targets were detected by GUIDE-seq. Likewise, all three gene editing platforms were established in the GMP-grade CliniMACS Prodigy, achieving similar outcome to preclinical devices. Based on this gene editing comparative analysis, we concluded that  BCL11A  is the most clinically relevant approach while  HBG1/2  could represent a promising alternative for the treatment of β-hemoglobinopathies.

Comparative targeting analysis of KLF1, BCL11A, and HBG1/2 in CD34+ HSPCs by CRISPR/Cas9 for the induction of fetal hemoglobin