DeCure for Autosomal recessive severe congenital neutropenia due to CSF3R deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for autosomal recessive severe congenital neutropenia due to CSF3R deficiency — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleAutosomal recessive severe congenital neutropenia due to CSF3R deficiency maps to a 2-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for autosomal recessive severe congenital neutropenia due to csf3r deficiency is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
phosphatidylinositol-5-phosphate 4-kinase type 2 beta (PIP4K2B) — PIP4K2B is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet ampdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3X01 · 2.15 Å · ligand ADENOSINE MONOPHOSPHATE (AMP). Experimental structure, not a prediction.
What the evidence adds up to
In two unrelated families, three children with a homozygous missense mutation in CSF3R and one infant with compound heterozygous deletions all had severe congenital neutropenia with low peripheral neutrophils and life-threatening bacterial infections. Bone marrow showed full myeloid maturation despite the blood counts. None of the four patients responded to recombinant human G-CSF. The mutations caused loss of function of the G-CSF receptor, either by disrupting N-glycosylation and cell-surface localisation or by introducing frameshifts and premature stop codons.
Three additional patients from two families were later found to carry biallelic inactivating variants in CSF3, the gene encoding the ligand itself, rather than the receptor. Complete deficiency of CSF3 was confirmed by RT-PCR on fibroblast RNA. The resulting phenotype matched that seen in CSF3-deficient mice and zebrafish. This represents a second autosomal recessive form of severe congenital neutropenia, this time due to absence of the cytokine rather than its receptor.
The 2014 discovery of CSF3R mutations validated mouse knockout models from the 1990s, but the clinical consequence is that standard G-CSF treatment fails in these patients. No alternative therapy is reported in these abstracts. The CSF3-deficient patients likewise lack any described treatment response.
What remains missing is any trial of alternative myeloid growth factors or haematopoietic stem cell transplantation in these specific genotypes, any systematic screening for CSF3 or CSF3R mutations in G-CSF-unresponsive neutropenia, and any patient registry large enough to stratify outcomes by mutation type.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Blood · 2014 · 89 citations · open access
Inherited biallelic CSF3R mutations in severe congenital neutropenia
AbstractSevere congenital neutropenia (SCN) is characterized by low numbers of peripheral neutrophil granulocytes and a predisposition to life-threatening bacterial infections. We describe a novel genetic SCN type in 2 unrelated families associated with recessively inherited loss-of-function mutations in CSF3R, encoding the granulocyte colony-stimulating factor (G-CSF) receptor. Family A, with 3 affected children, carried a homozygous missense mutation (NM_000760.3:c.922C>T, NP_000751.1:p.Arg308Cys), which resulted in perturbed N-glycosylation and aberrant localization to the cell surface. Family B, with 1 affected infant, carried compound heterozygous deletions provoking frameshifts and premature stop codons (NM_000760.3:c.948_963del, NP_000751.1:p.Gly316fsTer322 and NM_000760.3:c.1245del, NP_000751.1:p.Gly415fsTer432). Despite peripheral SCN, all patients had morphologic evidence of full myeloid cell maturation in bone marrow. None of the patients responded to treatment with recombinant human G-CSF. Our study highlights the genetic and morphologic SCN variability and provides evidence both for functional importance and redundancy of G-CSF receptor-mediated signaling in human granulopoiesis.
British Journal of Haematology · 2023 · 9 citations · open access
Human ‘knockouts’ of <i>CSF3</i> display severe congenital neutropenia
AbstractColony-stimulating factor 3 (CSF3) is a key factor in neutrophil production and function, and recombinant forms have been used clinically for decades to treat congenital and acquired neutropenia. Although biallelic inactivation of its receptor CSF3R is a well-established cause of severe congenital neutropenia (SCN), no corresponding Mendelian disease has been ascribed to date to CSF3. Here, we describe three patients from two families each segregating a different biallelic inactivating variant in CSF3 with SCN. Complete deficiency of CSF3 as a result of nonsense-mediated decay (NMD) could be demonstrated on RT-PCR using skin fibroblasts-derived RNA. The phenotype observed in this cohort mirrors that documented in mouse and zebrafish models of CSF3 deficiency. Our results suggest that CSF3 deficiency in humans causes a novel autosomal recessive form of SCN.
AbstractIn this issue of Blood , Triot et al describe a novel genetic subtype of severe congenital neutropenia (SCN) characterized by inherited, biallelic loss-of-function mutations in the granulocyte–colony-stimulating factor (G-CSF) receptor gene, CSF3R . 1 These findings expand the spectrum of pathogenic CSF3R mutations in humans and provide long overdue validation of mouse models generated in the 1990s.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
