ELANE, which encodes neutrophil elastase, is closely associated with neutrophil maturation and various disease conditions. Mutations in ELANE are the common cause of cyclic neutropenia (CyN) and severe congenital neutropenia (SCN) [2,4,5]. These neutropenias are characterized by abnormal neutrophil counts and maturation arrest in the bone marrow, highlighting the importance of ELANE in normal neutrophil development.

Pooled CRISPR screen in human hematopoietic stem and progenitor cells (HSPCs) showed that gene editing of ELANE early exons led to nonsense-mediated decay (NMD), overcoming neutrophil maturation arrest in HSPCs from ELANE-mutant SCN patients, while terminal exon frameshift alleles mimicking SCN-associated mutations recapitulated the maturation arrest [3]. In another study, CRISPR-Cas9D10A nickases were used to inhibit ELANE mRNA expression by introducing breaks at the ELANE promoter TATA box, effectively restoring defective neutrophil differentiation of ELANE-CN CD34+ HSPCs in vitro and in vivo [1].

In conclusion, ELANE plays a crucial role in neutrophil maturation. The study of ELANE-mutant models, especially through gene-editing techniques, has provided insights into the molecular mechanisms of ELANE-associated neutropenias. These findings may contribute to the development of gene-therapy approaches for treating severe congenital neutropenia [1,3].