DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for X-linked severe congenital neutropenia — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleX-linked severe congenital neutropenia maps to a 3-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 x-linked 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
WASP actin nucleation promoting factor (WAS) — WAS 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 2A3Z · 2.078 Å · ligand ADENOSINE-5'-TRIPHOSPHATE (ATP). Experimental structure, not a prediction.
What the evidence adds up to
X-linked neutropenia (XLN) is a rare form of congenital neutropenia caused by inherited gain-of-function mutations of WAS. Two cases from the original L270P XLN kindred evolved to myelodysplastic syndrome or acute myeloid leukaemia, with acquisition of CSF3R mutations and monosomy 7. This shows that leukemic transformation with these genetic changes is not restricted to classical autosomal congenital neutropenia but can also occur in other inherited neutropenia genotypes.
Severe congenital neutropenia comprises several genetically distinct entities. Mutations have been identified in the neutrophil elastase gene ELA2, in the antiapoptotic gene HAX1, and in other genes. In a genetic testing programme conducted between July 2019 and April 2025, 3,088 individuals were tested. 355 (11.5%) received a positive molecular result. 93 (3%) were diagnosed with severe congenital neutropenia with pathogenic or likely pathogenic variants in 11 genes: ELANE (48 patients), CXCR4 (18 patients), G6PC3 and TCIRG1 (5 patients each), and GATA2, HAX1, TAZ, WAS, CSF3R, VPS13B, and CD40LG. 267 (8.6%) received a positive result for another primary immunodeficiency.
The programme described one male patient found at age 11 to harbour a CXCR2 variant associated with severe congenital neutropenia due to CXCR2 deficiency. He was enrolled in a Phase 1b and Phase 2 clinical trial investigating mavorixafor in participants with congenital neutropenia and chronic neutropenia disorders. He was receiving G-CSF background therapy, and during the study the G-CSF dosage was reduced by 50% by month 4 and maintained through month 6. Despite this reduction, his absolute neutrophil count remained at or above approximately 1000 cells/µL throughout the study.
What is still missing is evidence from larger, controlled trials that can confirm whether genetic stratification leads to improved outcomes beyond the single case reported. The programme itself is sponsored by a pharmaceutical company, and the trial described is investigational. No data on long-term survival, infection rates, or prevention of leukaemic transformation are provided for any drug.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Haematologica · 2009 · 38 citations · open access
G-CSF receptor (CSF3R) mutations in X-linked neutropenia evolving to acute myeloid leukemia or myelodysplasia
AbstractX-linked neutropenia (XLN) is a rare form of Congenital Neutropenia (CN) caused by inherited gain-of-function mutations of WAS. Here we report 2 cases of the original L270P X-linked neutropenia kindred that evolved to MDS or AML, with acquisition of G-CSFR (CSF3R) mutations and monosomy 7. Thus, leukemic transformation with acquisition of CSF3R mutations and monosomy 7 is not restricted to classical congenital neutropenia with autosomal inheritance, but can also occur in other genotypes of inherited neutropenia.
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.
Neutropenia in pediatric hematology/oncology practice
AbstractAcquired neutropenia is one of the most common conditions in pediatric hematology practice. These conditions usually are benign. In contrast, congenital neutropenia are rare conditions, but in the absence of pathogenic therapy can cause fatal complications. Approach to the differential diagnosis and management of these patients are discussed in this review.
Role of genetic testing in diagnosing patients with severe congenital neutropenia: Results from PATH4WARD genetic testing program
AbstractAbstract Patients with suspected severe congenital neutropenia (SCN) frequently exhibit a wide spectrum of clinical manifestations, which can complicate timely and accurate diagnosis. Following the exclusion of acquired etiologies, genetic testing should be incorporated into the diagnostic evaluation for individuals with a clinical suspicion of congenital neutropenia. In this report, we present findings from PATH4WARD, an X4 Pharmaceuticals-sponsored genetic testing initiative aimed at supporting early and precise molecular diagnosis of primary immunodeficiencies (PIDs) associated with neutropenia. Identification of these conditions may facilitate appropriate clinical management, initiation of approved therapeutic interventions, and consideration for enrollment in appropriate interventional clinical trials. The PATH4WARD program, conducted between July 2019 and April 2025, utilized a next-generation sequencing (NGS) approach with panel expansion over time. Initially launched with a 23-gene SCN panel in 2019, the testing was expanded to a 407-gene primary immunodeficiency (PID) panel in 2021, and further extended in 2022 to a comprehensive 574-gene panel encompassing both PID and cytopenia-associated genes. Variant interpretation was performed using Sherloc, an evidence-based classification system based on the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines. Of 3,088 individuals who underwent testing, 355 (11.5%) received a positive molecular test result. 93 (3%) patients were diagnosed with SCN with pathogenic or likely pathogenic variants in 11 unique genes (ELANE, CXCR4, G6PC3, TCIRG1, GATA2, HAX1, TAZ, WAS, CSF3R, VPS13B, and CD40LG). The most common type of SCN-causing variants identified were ELANE (48 patients), followed by CXCR4 (18 patients), G6PC3, and TCIRG1 (5 patients each). 267 (8.6%) patients received a positive molecular test result for another type of PID (5 of these patients received positive test results for both SCN and another PID). To illustrate the clinical utility of genetic testing in guiding diagnosis and treatment decision making, we present the case of a patient with neutropenia who underwent genetic evaluation through the PATH4WARD program. In 2022, at age 11 years, the male patient was found to harbor CXCR2 c.865C>T, p.Arg289Cys, a variant associated with SCN due to CXCR2 deficiency.1 In 2023 the patient was enrolled in a Phase 1b and Phase 2 clinical trial investigating mavorixafor in participants with congenital neutropenia and chronic neutropenia disorders, including chronic idiopathic neutropenia (NCT04154488). The participant was receiving G-CSF background therapy for chronic neutropenia, and during the study, the investigator and participant chose to reduce the G-CSF dosage, achieving a 50% reduction by month 4, which was maintained through month 6. Despite this substantial reduction in G-CSF, the patient's absolute neutrophil count remained at or above approximately 1000 cells/µL throughout the study. This case highlights the value of genetic testing in establishing a molecular diagnosis and enabling access to investigational agents through clinical trial participation, with the potential to improve clinical outcomes. Reference:Marin-Esteban, et al. Haematologica. Mar 1 2022;107(3):765-769.
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.
