Cell reports. MedicineSep 27, 2025

Using multiple precise gene edits in BCL11A control regions to treat sickle cell disease

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

Multiplex base editing of BCL11A enhancers may offer a safer HbF-reactivation strategy for sickle cell disease.

Evidence

This preclinical gene-editing study tested base editors in HSPCs and in vivo, targeting the +58-kb and +55-kb BCL11A enhancers to raise HbF while reducing DSBs and rearrangements.

Caveat

The abstract reports preclinical HSPC and in vivo results, not patient outcomes or long-term clinical safety.

Simplified

Sickle cell disease (SCD) is a genetic anemia caused by the production of an abnormal adult hemoglobin. Elevated levels of fetal hemoglobin (HbF) in adulthood reduce disease severity. A promising therapy involves the treatment of hematopoietic stem/progenitor cells (HSPCs) with CRISPR-Cas9 to downregulate the HbF repressor BCL11A via generation of double-strand breaks (DSBs) in the +58-kb enhancer. To improve safety and HbF induction, we use base editors to target both the +58-kb and +55-kb enhancers without generating DSBs. We dissect key DNA motifs recognized by transcriptional activators and identify critical nucleotides. Multiplex base editing efficiently disrupts these sites, reactivating HbF to levels exceeding those achieved with CRISPR-Cas9-induced editing, while minimizing DSBs and genomic rearrangements. Base editing is effective in long-term repopulating HSPCs and results in robust HbF reactivation in vivo. These findings demonstrate that multiplex base editing of BCL11A enhancers is a safe, efficient, and durable strategy to treat SCD.

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Using multiple precise gene edits in BCL11A control regions to treat sickle cell disease

Abstract

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