DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for erythrocytosis, familial, 6 — 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, 6 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
approvedPazopanibApproved drug
Structures already discussed alongside erythrocytosis, familial, 6 in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
hemoglobin subunit beta (HBB) — HBB is one of the genes in this disease's Open Targets module — part of the target space DeCure's repurposing candidates point at. The protein backbone is drawn as a cartoon. The structure has protoporphyrin ix containing fe bound in it, shown as sticks.
Loading structure…
helix sheet hemdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1DXT · 1.7 Å · ligand PROTOPORPHYRIN IX CONTAINING FE (HEM). Experimental structure, not a prediction.
What the evidence adds up to
Erythrocytosis is a blood disorder characterised by increased red blood cell mass. Familial erythrocytosis type 1 is associated with hypersensitivity to erythropoietin due to variants in EPOR, types 2–5 with defects in oxygen-sensing pathways (VHL, EGLN1, EPAS1, EPO), and types 6–8 with increased haemoglobin–oxygen affinity (HBB, HBA1, HBA2, BPGM). In more than 70% of patients the condition remains labelled idiopathic, and in more than 60% of cases the genetic cause remains undiagnosed even after targeted testing of nine genes in the oxygen-sensing, erythropoietin-signal-transduction and haemoglobin-affinity pathways. A 1979 report of an English family with erythrocytosis across three generations found only a moderate increase in red cell mass in some affected members, accompanied by unusually low plasma volume, normal haemoglobin oxygen affinity, and an essentially normal pattern of serum and urinary erythropoietin during venesection. Venesection produced transient clinical benefit in the older patient but no obvious change in the younger ones.
Four novel EPOR mutations discovered in patients with primary familial and congenital polycythaemia (PFCP, familial erythrocytosis type 1) were studied in an in vitro system using chimeric EGFR–EPOR receptors stably transfected into the EPO-dependent human erythroleukemia cell line UT7. The mutations were two deletions leading to frameshifts and truncations (Del1387-1390 and Del1378-1412), a nonsense mutation (C1371A) resulting in truncation, and a missense mutation (G1445A) substituting arginine 437 for histidine. UT7 cells expressing any of the four mutated chimeric receptors proliferated even at very low EGF concentrations (0.01 ng/ml), whereas cells expressing the wild-type chimera did not. The mutated chimeras also displayed enhanced growth. Each mutation differentially affected receptor signalling and metabolism: Del1387-1390 showed higher levels of glycan-mature protein, slower degradation, and slower attenuation of EGF-induced pSTAT5; Del1378-1412 exhibited slower degradation and higher glycan-mature protein; C1371A displayed higher cell surface levels, slower degradation, and constitutive activation of STAT5; G1445A mediated slower attenuation of EGF-induced MAPK/ERK signalling. This is the first description of a missense EPOR mutation associated with receptor over-activity and a polycythaemic phenotype.
Additional molecular mechanisms proposed to influence erythrocytosis pathways include mRNA transcriptional regulation, post-translational modifications, membrane transport, regulation of signal transduction, glucose metabolism and iron homeostasis. These were identified through a literature review and in silico tools, but remain theoretical. The genetic background is heterogeneous, and the causes of disease are not fully discovered. What is still missing is systematic application of next-generation sequencing in clinical practice to detect variants in a single rapid test, and prospective studies that stratify patients by genotype to determine whether any intervention alters clinical outcomes. No drug treatment is tested or recommended in these abstracts.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
PubMed · 2021 · 16 citations · open access
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 Oncology Pharmacy Practice · 2021 · 8 citations
Sustained erythrocytosis due to the use of Lenvatinib
AbstractINTRODUCTION: Tyrosine kinase inhibitors have become the mainstay of treatment for many malignancies, but their use can be accompanied by unusual and often puzzling side effects. CASE REPORT: We describe herein a 64-year-old patient who developed a robust and sustained erythrocytosis shortly after starting treatment with lenvatinib. Our patient also experienced elevated blood pressure, mucositis, and hand-foot syndrome that are not uncommonly seen with this agent. The clinico-laboratory work-up suggested that lenvatinib was the likely culprit in this case. MANAGEMENT & OUTCOME: Lenvatinib had to be discontinued due to suboptimal tolerance and a short-lived response. With the discontinuation of lenvatinib, hemoglobin trended downwards and subsequently resolved. A score of 6 on the Naranjo nomogram supported a probable causality relationship between lenvatinib and the observed erythrocytosis. DISCUSSION: Erythrocytosis has previously been described with sunitinub, sorafenib and pazopanib. The exact mechanism of this phenomenon is not known. It might increase the risk of venous and arterial thromboses in cancer patients that are already in a hypercoagulable state due to cancer itself. In addition, laboratory work-up for polycythemia may prove extensive and costly. Therefore, clinicians need to be aware of this important side effect of tyrosine kinase inhibitors.
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.
Polycythemia-Inducing Mutations In The Erythropoietin Receptor (EPOR): Mechanism and Function Elucidated By EGFR– EPOR Chimeras
AbstractAbstract Absolute erythrocytosis are rare disorders characterized by a significant increase of the red blood cell mass which is reflected by an increased number of circulating erythrocytes, high hematocrit and hemoglobin. Primary familial and congenital polycythemia (PFCP, familial erythrocytosis type 1, OMIM #133100) is an inherited form of this disease, caused by erythropoietin (EPO) hypersensitivity of erythroid precursor cells. A number of mutations in the intracellular region of the EPO receptor (EPOR) have been found in recent years to be associated with manifestation of the disease. The objective of the study was to explore the mechanisms by which these mutations in the cytosolic domain of EPOR may induce the erythrocytosis phenotype. The research strategy was to construct chimeric receptors that contain the extracellular and transmembrane regions of the human epidermal growth factor receptor (EGFR) fused to the cytosolic domain of the human EPOR. The moiety of the EPOR intracellular region was mutated according to 4 novel mutations discovered in the cytosolic domain of the EPOR in PFCP patients. This design enabled EPOR signaling to be triggered by EGF binding to the extracellular domain of the chimera. The working hypothesis was that since the cytosolic, EPOR region of the chimera was generated based on mutations discovered in PFCP patients, any differences in the chimera-related effects would be specifically attributed to the mutations. The experiments were performed in an in vitro system, in which the Wild-Type (WT) EGFR– EPOR and the EGFR– EPOR chimeras bearing the mutated EPOR cytosolic domain were stably transfected into the EPO-dependent human erythroleukemia cell-line UT7. As these cells lack the EGF receptor, the natural EPOR signaling can be avoided when the transfected cells are grown with, or activated by, EGF. Using this system we have analyzed 4 novel EPOR mutations discovered in PFCP patients: 2 deletions which lead to frameshifts, premature stop codons and truncations (Del1387-1390 and Del1378-1412), a nonsense mutation (C1371A) which results in truncation of the receptor, and a missense mutation (G1445A) which results in the substitution of arginine 437 to histidine. A panel of experiments was performed on UT7 cells expressing the WT EGFR-EPOR chimera or EGFR– EPOR chimeras bearing the EPOR cytosolic PFCP-associated mutations. We addressed the degradation rates of the chimeric receptors, the kinetics of EGF induced STAT5 and MAPK/ERK signaling cascades and the levels of glycan-maturation and cell-surface expression of the chimeras. Cell viability analysis revealed that UT7 cells expressing either one of the 4 mutated chimeric receptors proliferated even under very low (0.01 ng/ml) EGF concentrations, as opposed to cells expressing the WT chimera, which did not proliferate under these conditions. UT7 cells expressing the mutated chimeras also displayed enhanced growth, which may indicate that indeed the mutations are the underlying cause of PFCP. Notably, our findings are the first description of a missense EPOR mutation that is associated with over-activity of the EPOR and with development of a polycythemic phenotype. Furthermore, we found that each of the 4 EPOR mutations differentially affected signaling and metabolism of the chimeric receptors. Hence, (i) Del1387-1390, showed higher levels of glycan-mature protein, as well as slower degradation rates, and conferred slower attenuation of EGF-induced pSTAT5. (ii) Del1378-1412 exhibited slower degradation rates and higher levels of glycan-mature protein. (iii) The nonsense mutation, C1371A, displayed higher cell surface levels, slower degradation rates and relayed constitutive activation of STAT5. (iv) The missense mutation, G1445A, mediated a slower attenuation of EGF induced MAPK/ERK signaling. Our study supports the evidence regarding the role of the cytosolic region of EPOR in metabolism of the receptor and sheds new light on the mechanisms underlying erythrocytosis-inducing mutations in the EPOR. HH, MFMcM, MJP, CB, HC and DN are members MPN&MPNr-EuroNet (COST Action BM0902) Disclosures: No relevant conflicts of interest to declare.
Case Reports in Hematology · 2022 · 0 citations · open access
Unexplained Hematocrit Increase after Therapeutic Phlebotomy in a Patient with Marked Erythrocytosis
AbstractWe report a patient with hereditary erythrocytosis who underwent a therapeutic phlebotomy and had a post-phlebotomy hematocrit that was higher than the pre-phlebotomy hematocrit. We could not discern a reason for this hematocrit increase after phlebotomy. Instead of performing another phlebotomy, we performed an automated red cell depletion via an apheresis instrument. This procedure is essentially a red cell exchange, but 5% albumin is used as the replacement fluid instead of red blood cells. The patient's hematocrit decreased from 80% to 39% after three consecutive daily red cell depletion procedures. We share our experience to report the unusual finding of a patient's hematocrit that increased with phlebotomy and to raise awareness of the red cell depletion procedure.
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.
