Abstract
Genome editing is potentially a curative technique available to all individuals with β-hemoglobinopathies, including sickle cell disease (SCD). Fetal hemoglobin (HbF) inhibits sickle hemoglobin (HbS) polymerization, and it is well described that naturally occurring hereditary persistence of HbF (HPFH) alleviates disease symptoms; therefore, reawakening of developmentally silenced HbF in adult red blood cells (RBCs) has long been of interest as a therapeutic strategy. Recent advances in genome editing platforms, particularly with the use of CRISPR-Cas9, have paved the way for efficient HbF induction through the creation of artificial HPFH mutations, editing of transcriptional HbF silencers, and modulating epigenetic intermediates that govern HbF expression. Clinical trials investigating BCL11A enhancer editing in patients with β-hemoglobinopathies have demonstrated promising results, although follow-up is short and the number of patients treated to date is low. While practical, economic, and clinical challenges of genome editing are well recognized by the scientific community, potential solutions to overcome these hurdles are in development. Here, we review the recent progress and obstacles yet to be overcome for the most effective and feasible HbF reactivation practice using CRISPR-Cas9 genome editing as a curative strategy for patients with SCD.
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Given the ability of fetal hemoglobin (HbF) to inhibit sickle hemoglobin polymerization, HbF reactivation by the creation of naturally occurring HbF-associated mutations, editing HbF repressors/their binding site, or epigenetic intermediates using CRISPR-Cas9 are promising. Recent clinical data are encouraging; nevertheless, long-term follow-up is lacking, and genome editing safety and efficacy concerns remain.