Beyond repressor disruption: Designing activator motifs to boost fetal hemoglobin

Fetal hemoglobin (HbF) reactivation is now a powerful and clinically validated strategy for sickle cell disease (SCD). Many genome-editing approaches achieve this by disrupting regulatory sequences involved in γ-globin silencing, such as the BCL11A erythroid enhancer. In a recent issue of Molecular Therapy Nucleic Acids, Chalumeau et al.1 replaced the BCL11A binding site in the HBG1/2 promoters with a composite TAL1:GATA1 activating motif rather than only disrupting a repressor site. The edited promoters supported robust γ-globin expression and reduced sickling in erythroid cells derived from SCD hematopoietic stem and progenitor cells (HSPCs).