DeCure for Autosomal dominant severe congenital neutropenia
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for autosomal dominant severe congenital neutropenia — screening already-approved drugs against its 4-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleAutosomal dominant severe congenital neutropenia maps to a 4-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 dominant severe congenital neutropenia 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
ClpB family mitochondrial disaggregase (CLPB) — CLPB 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 atpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7XBK · 3.7 Å · ligand ADENOSINE-5'-TRIPHOSPHATE (ATP). Experimental structure, not a prediction.
What the evidence adds up to
Severe congenital neutropenia is a heterogeneous disorder of haematopoiesis defined by a maturation arrest of granulopoiesis at the promyelocyte stage and peripheral blood absolute neutrophil counts below 0.5 x 10⁹/L. The estimated incidence is 1 in 200,000 individuals of European descent. Two major inheritance subtypes are described: an autosomal dominant trait with neutrophil elastase (ELA2) mutations accounting for about 60% of patients, and an autosomal recessive trait comprising roughly 30% of patients. After 10 years of observation the cumulative incidence for leukaemia is 21%, and acquired granulocyte colony-stimulating factor receptor mutations are detected in approximately 80% of congenital neutropenia patients who developed acute myeloid leukaemia.
Downregulation of lymphoid enhancer-binding factor 1 and its target genes has been proposed as a common pathophysiological mechanism across all congenital neutropenia patients. In autosomal recessive severe congenital neutropenia, homozygous mutations in the antiapoptotic gene HAX1 have been identified. Ongoing linkage studies suggest that additional, as yet unidentified, genes may be involved. In some patients congenital neutropenia is not isolated but associated with lymphoid immunodeficiency and pigmentation defects, including Chédiak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2, and deficiency of the endosomal adaptor p14, all originating from mutations in lysosome-related proteins.
A five-generation family segregating a novel single nucleotide variant in TCIRG1 has been reported, with perfect cosegregation of the variant with congenital neutropenia: all 11 affected individuals carried the variant, none of the unaffected did. Western blot analysis showed reduced levels of TCIRG1 protein in affected individuals compared to healthy controls. Two unrelated patients with severe congenital neutropenia, identified by independent investigators, were heterozygous for different rare, highly conserved, coding variants in TCIRG1. Despite these advances, the genetic basis for more than 30% of cases remains unknown.
What is still missing is a definitive genetic classification system that covers all patients, prospective studies linking specific genotypes to leukaemia risk, and clinical trials that stratify patients by molecular subtype to test whether targeted therapies can alter the natural history of the disease. Funding for long-term registry studies and functional validation of newly identified variants in animal models is also lacking.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Current Opinion in Hematology · 2007 · 82 citations
Severe congenital neutropenia: inheritance and pathophysiology
AbstractPURPOSE OF REVIEW: Severe congenital neutropenia is a heterogeneous disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10/l. In this review we summarize our current knowledge on inheritance and pathophysiolgy of congenital neutropenia. RECENT FINDINGS: There are two major subtypes of congenital neutropenia as judged by inheritance: autosomal dominant trait defined by neutrophil elastase mutations consisting of 60% of patients and autosomal recessive trait comprising approximately 30% of patients. This genetic heterogeneity suggests that several pathologic mechanisms may lead to the same phenotype due to downregulation of common myeloid transcription factors. Lymphoid enhancer-binding factor 1 is the most promising candidate, as its abrogation together with downregulation of lymphoid enhancer-binding factor 1 target genes is compatible with this phenotype. Congenital neutropenia is considered as a preleukemic syndrome, since after 10 years of observation the cumulative incidence for leukemia is 21%. Acquired granulocyte colony-stimulating factor receptor mutations are detected in approximately 80% of congenital neutropenia patients who developed acute myeloid leukemia. SUMMARY: Congenital neutropenia is a congenital disorder of hematopoiesis inherited by autosomal dominant or recessive traits. Downregulation of lymphoid enhancer-binding factor 1 is involved in the pathophysiology of all congenital neutropenia patients. Congenital neutropenia patients with acquired granulocyte colony-stimulating factor receptor mutations define a group with high risk for development of leukemia.
Current Opinion in Rheumatology · 2007 · 29 citations
Severe congenital neutropenia: new genes explain an old disease
AbstractPURPOSE OF REVIEW: This review summarizes the recent advances in the diagnosis and molecular characterization of isolated and syndromal forms of severe congenital neutropenia. RECENT FINDINGS: It has become evident that severe congenital neutropenia comprises several genetically distinct entities. In 1999, mutations were identified in the neutrophil elastase gene ELA2. ELA2 mutations have been found in cyclic, sporadic and autosomal dominant neutropenia. Recently, homozygous mutations in the antiapoptotic gene HAX1 were found in patients with autosomal recessive severe congenital neutropenia. Ongoing linkage studies suggest that more and, as yet unidentified, genes may be involved in the pathophysiology of severe congenital neutropenia. In other patients, congenital neutropenia is not an isolated finding but is associated with other abnormalities, in particular, lymphoid immunodeficiency and pigmentation defects such as Chédiak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2, or deficiency of the endosomal adaptor p14. The molecular identification of these disorders originating from mutations in lysosome (related) proteins has advanced our knowledge of intracellular protein trafficking. SUMMARY: Recent insights into the molecular etiology of severe congenital neutropenia provide the opportunity for a definitive genetic classification system. Based on this knowledge, disease-related risks may be recognized and optimized therapeutic options may become available.
AbstractIn 1950 Rolf Kostmann discovered autosomal recessive severe congenital neutropenia and for more than 50 years its molecular etiology has remained enigmatic. In the last years, however, there have been impressive advances in this field. In this perspective article, Dr. Klein summarizes our current knowledge of the molecular basis of congenital neutropenia. See related paper on page 1449.
Dialnet (Universidad de la Rioja) · 2009 · 3 citations
PRODUCTIONS OF GREEK AND ROMAN DRAMA ON THE CZECH STAGE 2001-2009
AbstractSevere congenital neutropenia (SCN) is a rare hematopoietic disorder, with estimated incidence of 1 in 200,000 individuals of European descent, many cases of which are inherited in an autosomal dominant pattern. Despite the fact that several causal genes have been identified, the genetic basis for >30% of cases remains unknown. We report a five-generation family segregating a novel single nucleotide variant (SNV) in TCIRG1. There is perfect cosegregation of the SNV with congenital neutropenia in this family; all 11 affected, but none of the unaffected, individuals carry this novel SNV. Western blot analysis show reduced levels of TCIRG1 protein in affected individuals, compared to healthy controls. Two unrelated patients with SCN, identified by independent investigators, are heterozygous for different, rare, highly conserved, coding variants in TCIRG1.
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.
