DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for erythrocytosis, familial, 4 — 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 moduleErythrocytosis, familial, 4 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 erythrocytosis, familial, 4 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
endothelial PAS domain protein 1 (EPAS1) — EPAS1 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 furan-2-ylmethyldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3H82 · 1.5 Å · ligand N-(furan-2-ylmethyl)-2-nitro-4-(trifluoromethyl)aniline (020). Experimental structure, not a prediction.
What the evidence adds up to
A 1998 report describes an English boy with familial erythrocytosis, high haemoglobin, and low serum erythropoietin, in whom sequencing of the erythropoietin receptor gene found a de novo G-to-A transition at nucleotide 6002, creating a stop codon at amino acid 439 and deleting 70 carboxy-terminal residues. The same mutation had arisen independently in a Finnish family. The authors recommend that patients with unexplained erythrocytosis and low serum Epo be investigated for EpoR mutations.
Two 2021 reviews summarise the genetic landscape of erythrocytosis. Familial erythrocytosis type 1 is linked to EPOR variants causing hypersensitivity to erythropoietin; types 2–5 involve oxygen-sensing pathway defects (VHL, EGLN1, EPAS1, EPO); types 6–8 involve increased haemoglobin–oxygen affinity (HBB, HBA1, HBA2, BPGM). The majority of polycythaemia vera cases carry acquired JAK2 variants. However, in more than 70% of patients with erythrocytosis the cause remains idiopathic, and in more than 60% of cases directed genetic testing of nine known genes still yields no diagnosis. One review used in silico tools to propose additional candidate mechanisms — mRNA transcriptional regulation, post-translational modifications, membrane transport, signal transduction, glucose metabolism, and iron homeostasis — but these remain theoretical.
A 1979 report of a three-generation English family with erythrocytosis found only a moderate increase in red cell mass, accompanied by unusually low plasma volume. Haemoglobin oxygen affinity was normal. Serum and urinary erythropoietin responses to serial venesection followed an essentially normal pattern. Venesection produced transient clinical benefit in the oldest patient but no obvious change in the younger ones.
What is still missing is a diagnostic test that can identify the genetic cause in the majority of patients who currently remain labelled idiopathic. The proposed new molecular pathways have not been validated in patient cohorts. No trial has tested whether targeting any of these pathways alters clinical outcomes. Patient stratification by genotype is not yet possible for most cases, and funding for systematic sequencing of large, well-phenotyped families is limited.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
British Journal of Haematology · 1998 · 49 citations · open access
Erythrocytosis due to a mutation in the erythropoietin receptor gene
AbstractFamilial erythrocytosis, associated with high haemoglobin levels and low serum erythropoietin (Epo), has been shown to co-segregate with a sequence repeat polymorphism at the 5' region of the erythropoietin receptor (EpoR) in a large Finnish family. We have investigated the cause of erythrocytosis in an English boy. Sequencing of the cytoplasmic region of the EpoR detected a de novo transition mutation of G to A at nucleotide 6002. This mutation resulted in the formation of a stop codon at amino acid 439 with the loss of 70 amino acids from the carboxy terminus. The mutation (G6002A) has arisen independently in a Finnish family and de novo in this English boy. Patients with unexplained erythrocytosis and low serum Epo levels should be investigated for EpoR mutations.
Erythrocytosis: genes and pathways involved in disease development.
AbstractErythrocytosis is a blood disorder characterised by an increased red blood cell mass. The most common causes of erythrocytosis are acquired and caused by diseases and conditions that are accompanied by hypoxaemia or overproduction of erythropoietin. More rarely, erythrocytosis has a known genetic background, such as for polycythaemia vera and familial erythrocytosis. The majority of cases of polycythaemia vera are associated with acquired variants in JAK2, while familial erythrocytosis is a group of congenital disorders. Familial erythrocytosis type 1 is associated with hypersensitivity to erythropoietin (variants in EPOR), types 2-5 with defects in oxygen-sensing pathways (variants in VHL, EGLN1, EPAS1, EPO), and types 6-8 with an increased affinity of haemoglobin for oxygen (variants in HBB, HBA1, HBA2, BPGM). Due to a heterogenic genetic background, the causes of disease are not fully discovered and in more than 70% of patients the condition remains labelled idiopathic.The transfer of next-generation sequencing into clinical practice is becoming a reality enabling detection of various variants in a single rapid test. In this review, we describe the current research on erythrocytosis gene variants and the mechanisms associated with disease development, along with the currently used diagnostic tests.
Journal of Pediatric Hematology/Oncology · 1998 · 9 citations
Congenital Erythrocytosis With Elevated Erythropoietin Level
AbstractPURPOSE: A child who was extensively evaluated for polycythemia is reported. Polycythemia, or erythrocytosis, is seen rarely in children. The mechanisms for congenital and/or familial erythrocytosis are discussed. PATIENT AND METHODS: A 10 1/2-year-old white girl was referred for evaluation of polycythemia, which was detected incidentally during an emergency room visit for a febrile illness. She underwent extensive evaluation to determine the cause of the polycythemia. The literature was reviewed to determine the occurrence of congenital and/or familial erythrocytosis in children and its various causes. RESULTS: Despite extensive evaluation, no specific cause of the erythrocytosis could be determined in our patient. The erythrocytosis appeared to be secondary to an inappropriately elevated serum erythropoietin concentration. Serum erythropoietin rose further after phlebotomy, suggesting nonautonomous hypersecretion. After a review of the literature, we hypothesize that she had an inappropriate erythropoietin expression related to an abnormality in the renal oxygen-sensing mechanism governing erythropoietin synthesis. DISCUSSION: A discussion of congenital and familial erythrocytosis is presented, and a review of the literature regarding the possible mechanisms causing erythrocytosis is included.
Molecular Pathways Involved in the Development of Congenital Erythrocytosis
AbstractPatients with idiopathic erythrocytosis are directed to targeted genetic testing including nine genes involved in oxygen sensing pathway in kidneys, erythropoietin signal transduction in pre-erythrocytes and hemoglobin-oxygen affinity regulation in mature erythrocytes. However, in more than 60% of cases the genetic cause remains undiagnosed, suggesting that other genes and mechanisms must be involved in the disease development. This review aims to explore additional molecular mechanisms in recognized erythrocytosis pathways and propose new pathways associated with this rare hematological disorder. For this purpose, a comprehensive review of the literature was performed and different in silico tools were used. We identified genes involved in several mechanisms and molecular pathways, including mRNA transcriptional regulation, post-translational modifications, membrane transport, regulation of signal transduction, glucose metabolism and iron homeostasis, which have the potential to influence the main erythrocytosis-associated pathways. We provide valuable theoretical information for deeper insight into possible mechanisms of disease development. This information can be also helpful to improve the current diagnostic solutions for patients with idiopathic erythrocytosis.
Scandinavian Journal of Haematology · 1979 · 6 citations
Familial Erythrocytosis
AbstractErythrocytosis was found in 3 generations of an English family. The red cell mass was only moderately increased in some of the affected members but was accompanied by an unusually low plasma volume. Oxygen affinity of Hb was normal. Changes in serum and urinary erythropoietin showed an essentially normal pattern throughout a series of venesections. Venesection produced some transient clinical benefit in the older patient but there was no obvious change in the younger ones.
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.
