DeCure for Congenital neutropenia-myelofibrosis-nephromegaly syndrome
DeCure's autonomous Nephrology AI scientist is researching a drug-repurposing hypothesis for congenital neutropenia-myelofibrosis-nephromegaly syndrome — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCongenital neutropenia-myelofibrosis-nephromegaly syndrome maps to a 1-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 congenital neutropenia-myelofibrosis-nephromegaly syndrome 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.
What the evidence adds up to
The abstracts describe congenital neutropenia as a rare, inherited disorder of low neutrophil counts and recurrent infections, with bone marrow showing a maturational arrest at the promyelocyte stage. Treatment is based on granulocyte colony stimulating factor (G-CSF) administration, and the dose required to obtain normal neutrophil levels and prevent fever and infections is higher in children with severe congenital neutropenia than in those with other neutropenias. However, two patients with severe congenital neutropenia were clinically unresponsive to G-CSF therapy, as reported in 1995. The prolonged survival of neutropenic patients receiving G-CSF has drawn attention to complications of treatment, including leukemic transformation, which is more typical of severe congenital neutropenia and Shwachman-Diamond patients, particularly those needing high G-CSF dosage.
Mutations in the HAX1 gene are associated with most cases of recessive autosomal severe congenital neutropenia, while ELA2 mutations are found in most autosomal dominant and sporadic cases. The HAX-1 protein acts as a regulatory step in apoptosis, providing evidence for severe congenital neutropenia as a disorder of programmed cell death. An inflammatory bone marrow milieu, with activated T-lymphocytes and pro-apoptotic mediators such as IFNgamma, TNFalpha, Fas-ligand and TGFbeta1, results in accelerated apoptosis of granulocytic progenitor cells in chronic idiopathic neutropenia, and decreased levels of the anti-inflammatory cytokine IL-10 further disturb the balance between survival and pro-apoptotic mediators. The diagnosis of congenital neutropenia includes many disorders of distinct origin and variable prognosis, and determining the underlying cause can be challenging.
No abstract mentions congenital neutropenia-myelofibrosis-nephromegaly syndrome specifically, nor any drug other than G-CSF. The abstracts do not report survival or response rates for any drug in this syndrome. In the absence of pathogenic therapy, congenital neutropenia can cause fatal complications. What is still missing for this specific syndrome is any published clinical trial data, any identified genetic or biochemical basis, and any evidence that G-CSF or any other drug alters its natural history. Patient stratification, dedicated funding, and prospective studies designed for this syndrome are absent from the literature.
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 Allergy and Clinical Immunology · 2004 · 50 citations
Congenital neutropenia: advances in diagnosis and treatment
AbstractPURPOSE OF REVIEW: A decade after the availability of hematopoietic growth factors, the long-term outcome of severe congenital neutropenia has dramatically changed. The prolonged survival of neutropenic patients receiving hematopoietic growth factors has drawn attention to the heterogeneity of this disease and to the complications of treatment. The dose of granulocyte colony stimulating factor that is required to obtain normal levels of circulating neutrophils and to prevent fever and infections is quite variable among patients, but is higher in children with severe congenital neutropenia than in those with other conditions of neutropenia. Moreover, leukemic transformation during treatment is not observed in all patients, but is more typical of severe congenital neutropenia and Shwachman-Diamond patients. RECENT FINDINGS: In recent years, the converging efforts of hematologists, immunologists and geneticists have led to the discovery of the genetic and biochemical basis of severe congenital neutropenia; cyclic neutropenia; warts, hypogammaglobulinemia, immunodeficiency, myelokathexis or WHIM syndrome and other rarer conditions associated to neutropenia. SUMMARY: Although the diagnosis of congenital neutropenia includes many disorders of distinct origin and variable prognosis, their treatment is still based on granulocyte colony stimulating factor administration. Understanding the pathogenesis of these forms of neutropenia and their evolution will focus future studies on the mechanisms of normal and pathological myelopoiesis and on the development of the most appropriate treatment for each type of neutropenia.
Current Opinion in Hematology · 2008 · 46 citations
Chronic idiopathic neutropenias and severe congenital neutropenia
AbstractPURPOSE OF REVIEW: Chronic idiopathic and severe congenital neutropenias are rare disorders for which recent discoveries have highlighted mechanisms and consequences. RECENT FINDINGS: An inflammatory bone marrow milieu has been shown to be a major contributor to the pathophysiology of chronic idiopathic neutropenia. Activated T-lymphocytes with myelosuppressive properties and pro-apoptotic mediators, such as IFNgamma, TNFalpha, Fas-ligand and TGFbeta1 result in accelerated apoptosis of granulocytic progenitor cells. Decreased levels of the anti-inflammatory cytokine IL-10 further disturb the balance between survival and pro-apoptotic mediators in chronic idiopathic neutropenia. Mutations in the HAX1 gene are associated with most cases of recessive autosomal severe congenital neutropenia, while ELA2 mutations are found in most cases of autosomal dominant and sporadic cases. The role of HAX-1 protein as a regulatory step in apoptosis provides further evidence for severe congenital neutropenia as a disorder of programmed cell death. The preleukemic character of severe congenital neutropenia, particularly for patients with need for high granulocyte colony stimulating factor dosage, was recently emphasized. SUMMARY: Chronic idiopathic (or as recent data suggest, immunologic) and severe congenital neutropenias provide intriguing models for better understanding of regulation of myelopoiesis. Similarities and differences between the two disorders might help to dissect these regulatory events.
British Journal of Haematology · 1995 · 13 citations
Severe congenital neutropenia unresponsive to G‐CSF
AbstractSevere congenital neutropenia (SCN) is an inherited disorder characterized by severe neutropenia and recurrent infections from an early age, with bone marrow showing a maturational arrest of granulopoiesis at the promyelocyte stage. Since the introduction of G-CSF therapy the prognosis for affected children has improved dramatically. We describe two patients with SCN who were clinically unresponsive to G-CSF therapy. The results of in-vitro colony assays from these two patients are presented together with the results from the mother of one of these patients who also has a chronic neutropenia, and a further child with SCN who responded to treatment with G-CSF.
Clinical Hematology International · 2021 · 13 citations · open access
How to Make the Right Diagnosis in Neutropenia
AbstractIsolated neutropenia without anemia or thrombocytopenia is a common clinical problem. The etiology of neutropenia may vary from transient bone marrow suppression, caused by self-limited viral illnesses, to previously undiagnosed congenital syndromes or serious systemic diseases. Consequently, determining the underlying cause of neutropenia and what treatment is required can be challenging. Acquired neutropenia is common and most of the times an etiologic factor can be found. Congenital neutropenia (CN) is rare, and we still have a lot to learn from mutational analysis as to the exact role of gene abnormalities in the pathogenesis of these complex diseases. This mini-review discusses a proposed approach to neutropenia in the adult patient.
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.
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.
