Current clinical gene therapy trials for β-thalassaemia and sickle cell disease (SCD) rely on addition of a functional but reduced β-globin gene to the genome of haematopoietic stem and progenitors cells (HSPCs) of patients [↗]. Early results from the latest trial [↗] indicate that gene addition might be therapeutic even for severe forms of the disease, but concerns over safety and universal applicability remain, and alternative approaches are sought. Notably, individuals with elevated γ-globin levels (and thus hereditary persistence of fetal haemoglobin, HPFH) show extremely mild disease symptoms, spawning attempts to exploit the phenomenon by engineered activation of the endogenous γ-globin. Genome editing instead of gene addition might minimise the risk to patients and has therefore been taken up enthusiastically for preclinical studies [↗]. Using the technology to activate the endogenous γ-globin might moreover be applicable to all β-thalassaemia mutations and sickle cell disease alike.

Genome editing for therapeutic activation of γ-globin has recently seen two landmark papers advancing the field. In 2015, Canver et al. [↗] used genome editing with the CRISPR/Cas9 system to disrupt erythroid-specific expression of the γ-globin repressor BCL11A, achieving high levels of γ-globin in normal HSPCs in the process. A publication by Traxler et al. in Nature Medicine this August [↗] takes an alternative approach based on the same concept of sequence disruption, instead mimicking a naturally occurring HPFH mutation that introduces a 13-bp deletion in the γ-globin promoter [↗] (see mutation details in IthaGenes [↗]). Encouragingly, the study once again shows high levels of γ-globin induction and additionally demonstrates significant phenotypic correction of SCD HSPC-derived erythroid cells in culture. However, at the heart of high efficiencies in HSCPs in both studies are integrating lentiviral vectors for continued expression of the CRISPR/Cas9 elements; while this allows accumulation of correction events in culture, it also accumulates any unwanted (off-target) editing events and moreover also poses the same risk of insertional mutagenesis as gene-addition approaches. Although genome editing therefore still has some way to go towards clinical application for β-globinopathies, γ-globin induction appears to be one of the most promising paths to get there.