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Page 2 of 10 Mazur et al. Rare Dis Orphan Drugs J 2023;2:1 https://dx.doi.org/10.20517/rdodj.2022.12

[1-3]
infections, which occur early in life and can be life-threatening . Mutations of ELANE, the gene that
encodes neutrophil elastase (NE), are the most frequent cause of the inherited forms of neutropenia. Here
we review the current knowledge and emerging questions regarding how ELANE mutations contribute to a
shortage of, and/or dysfunction in neutrophils, and discuss possible strategies that target NE in the context
of neutropenia, focusing on ELANE gene editing and NE inhibitors. An overview of the full spectrum of
[3-5]
congenital neutropenic disorders is available elsewhere .
TYPES AND MAIN CAUSES OF NEUTROPENIA
Chronic neutropenia is a result of hereditary bone marrow-failure syndrome or an acquired deficit of
neutrophils . Whereas acquired neutropenia can occur secondary to autoimmune diseases, chemotherapy
[6]
or drug reactions, congenital (hereditary) neutropenia is a genetically heterogeneous group of primary
hematologic conditions that are mainly characterized by an anomalous neutrophil developmental program
(granulopoiesis) leading to insufficient production of mature neutrophils in the bone marrow and,
subsequently, low neutrophil counts in the bloodstream . In rare cases, such as WHIM syndrome, mature
[3]
[7]
neutrophils fail to exit the bone marrow, which also leads to peripheral neutropenia . Mutations in more
than 30 genes, such as ELANE, HAX1, G6PC3, SBDS, G6PT, CXCR4, TAZ, VPS45 or CXCR4 have been
identified so far as causative factors in inherited neutropenia . Neutrophil differentiation block observed
[3,8]
in congenital neutropenia can be associated with changes in the bone marrow, such as bone marrow
fibrosis; thus, it is not necessarily always an autonomous neutrophil cell phenomenon . However, cell-
[9]
intrinsic neutrophil maturation arrest, as a primary cause of neutropenia, has been reported for at least
some neutropenia genes . Despite the diverse underlying genetic defects that likely affect the function of
[3]
various subcellular compartments in neutrophil precursors, such as ER or mitochondria, the proteins
encoded by these genes may share (a) signaling pathway(s). Disruption of these pathways at different stages,
by defective products of neutropenia-causative genes, would then have similar hematopoietic
[3]
manifestations .
Mutations of the ELANE gene are the most common genetic aberration, accounting for about half of the
cases of severe congenital neutropenia (SCN). Whereas a hallmark of untreated SCN is either chronic or
severe quantitative and qualitative deficit in neutrophils , ELANE mutations are also the main cause of
[6]
milder cyclic neutropenia (CyN), characterized by episodes of neutrophil scarcity recurring in a cyclic
fashion, usually every 3 weeks. CyN-related ELANE mutations, which are either different from or overlap
with those occurring in SCN, are found in > 80% of CyN patients . The majority of SCN and CyN cases
[10]
arise due to germline mutations in the ELANE gene and are of a dominant nature, typically affecting only
one ELANE allele, and leaving the other ELANE allele intact . In addition to heterozygous, autosomal
[1]
dominant ELANE mutations, other models of inheritance, including single gene autosomal recessive, X-
linked and sporadic patterns, have also been described in congenital neutropenia in association with
different genes. For example, the HAX1 gene that causes SCN, also known as Kostmann disease, is an
autosomal recessive genetic mutation .
[3]

SCN and CyN remain incurable diseases, although in the majority of patients, these conditions can be kept
stable by regular, subcutaneous infusions of granulocyte colony-stimulating factor (G-CSF). Neutropenia
can evolve into myeloid malignances, such as myelodysplastic syndrome or acute myeloid leukemia
(MDS/AML). For effective therapy, patients with SCN typically require high doses of G-CSF. Those patients
who receive the largest doses of G-CSF appear to be at the greatest risk of progressing to myeloid
malignances [11,12] . In patients unresponsive to G-CSF or with an increased risk of MDS/AML, hematopoietic
stem cell transplantation might be a potential therapeutic option .
[3]