Programmable genomic DNA loci (BCL11A enhancer and HBB gene)

Programmable genomic DNA loci related to sickle cell disease (SCD) refer to specific chromosomal regions targeted by gene-editing technologies to restore normal hemoglobin function. The primary targets include the HBB gene, which harbors the causative mutation for SCD, and regulatory elements like the BCL11A erythroid-specific enhancer and the HBG1/HBG2 promoters [1][2]. By disrupting the BCL11A enhancer or modifying the HBG promoters, therapeutic agents can reactivate the production of fetal hemoglobin (HbF), which prevents the polymerization of sickle hemoglobin (HbS) [1][4]. These modifications are typically performed ex vivo in hematopoietic stem and progenitor cells (HSPCs) using CRISPR-Cas9, base editors, or lentiviral vectors before being re-infused into the patient [2][3]. The 'undisclosed target' mentioned in pipeline descriptions often refers to proprietary genomic sites intended to improve the efficiency of erythropoiesis or the persistence of edited cells [2]. This approach represents a curative paradigm for SCD by addressing the underlying genetic defect or its physiological consequences at the DNA level [1][4]. Sources: [1] Frangoul, H., et al. (2021). CRISPR-Cas9 Gene Editing for Sickle Cell Disease and Beta-Thalassemia. New England Journal of Medicine. [2] Beam Therapeutics. (2022). Pipeline and Platform Overview. [3] Cavazzana, M., et al. (2017). Gene Therapy in a Patient with Sickle Cell Disease. New England Journal of Medicine. [4] Steinberg, M. H. (2020). Fetal hemoglobin in sickle cell anemia. Blood Reviews.

Other names

BCL11A erythroid-specific enhancerHBB gene locusHBG1/HBG2 promoterFetal hemoglobin regulatory elementsBeta-globin gene cluster

Targeted genomic modification via CRISPR-Cas9, base editing, or lentiviral gene addition to disrupt repressors (e.g., BCL11A) or correct mutations (HBB), thereby restoring functional hemoglobin production.