DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Chuvash polycythemia — 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 moduleChuvash polycythemia 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 chuvash polycythemia 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
von Hippel-Lindau tumor suppressor (VHL) — VHL 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 2s,4rdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8QVU · 2.24 Å · ligand (2S,4R)-1-[(2S)-2-[4-[4-[(3S)-4-[4-[5-[(4S)-2-azanyl-3-cyano-4-methyl-6,7-dihydro-5H-1-benzothiophen-4-yl]-1,2,4-oxadiazol-3-yl]pyrimidin-2-yl]-3-methyl-1,4-diazepan-1-yl]butoxy]-1,2,3-triazol-1-yl]-3-methyl-butanoyl]-N-[(1R)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]-2-oxidanyl-ethyl]-4-oxidanyl-pyrrolidine-2-carboxamide (WYL). Experimental structure, not a prediction.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Blood · 2017 · 2 citations
Chuvash Polycythemia Patients from Afghanistan and Southern India Share a Common <i>VHL</i> Gene Haplotype. Support for Its Origin before Asians and Europeans Diverged
AbstractAbstract Chuvash polycythemia is a rare autosomal recessive hereditary disease, with affected homozygotes having decreased survival mainly because of increased incidence of stroke and other thrombotic complications. Intriguingly this risk may be augmented, rather than ameliorated, by phlebotomies (Sergueeva et al, Blood, 2015, and Haematologica 2017). Chuvash polycythemia is characterized by a C to T missense mutation of the von Hippel Lindau (VHL) gene at nucleotide 589 (VHLC589T, encoding VHLR200W). VHL is a negative regulator of hypoxia-inducible factor (HIF) α subunits. Homozygosity for VHLC589T upregulates hypoxic responses through constitutively augmented HIF signaling even in normoxia, resulting in an increase of erythropoiesis. Heterozygosity leads to only mild augmentation of hypoxia sensing. Chuvash polycythemia was first identified in people of the Chuvash region in Russia, where it has estimated heterozygosity frequency of 1.7%, likely due to a founder effect. The incidence of Chuvash polycythemia elsewhere is sporadic, and the condition is found in other ethnic groups, including northern Indians of Indo-European ethnicity and northern Europeans. Another hot spot of gene frequency was found among Italians on the island of Ischia. We previously published that VHLC589Thomozygotes from various parts of the world share a common VHL haplotype, and from the size of the shared haplotype, we could calculate that it originated from the same founder about 30-50,000 years ago (Liu, et al, Blood 2004). The same shared haplotype was also identified in Ischia in VHLC589Thomozygotes (Perrotta et al, Blood 2006). A single individual from Turkey had the VHLC589T mutation on a different haplotype (Turkish haplotype, Cario, et al, Heamatologica, 2005) demonstrating the existence of another independent founder of the VHLC589T mutation. Two polycythemic patients with VHLC589T mutation were recently referred to us, one from Afghanistan (among people using the Dravidian language who had frequent historical interactions with Turkey) and the other from southern India (the ethnicity of which is also Dravidian and distinct from Indo-European ethnicity). We hypothesized that the Chuvash polycythemia patients, who originated from Afghanistan and Southern India, might have the Turkish haplotype, strengthening support for two independent founders of this haplotype. We analyzed the VHL haplotype of these 2 individuals using 6 selected single nucleotide polymorphisms. Genomic DNA was isolated from granulocytes. Haplotype analysis was performed by Sanger Sequencing. We found that the Chuvash polycythemia patients from Afghanistan and Southern India shared the common Chuvash haplotype (Table). We conclude that the Chuvash haplotype is also present in VHLC589T homozygotes in Afghanistan and Southern India, suggesting that the VHLC589T mutation in these areas arose from the same common founder. The data support the notion that the Chuvash polycythemia VHL mutation originated relatively early in modern human evolution- possibly after humans moved from Africa- as it is present in different ethnic and racial groups (Europeans and Asians). This observation is compatible with the notion that VHLC589T heterozygosity provides some evolutionary advantage (present in various ethnic groups and did not disappear, i.e., absence of negative selection because of increased mortality of homozygotes). It has been shown that heterozygosity for VHLC589T provides some protection from anemia; it is likely that other evolutionary benefits remain to be identified (Miasnikova et al, Haematologica 2011). Yet, such an advantage is very mild (very low gene frequency worldwide of this mutation). These data provide additional evidence that support a VHLC589T origin before Asians and European diverged. Disclosures No relevant conflicts of interest to declare.
AbstractAbstract In Chuvash polycythemia, homozygosity for the 598 C-&gt;T mutation in the von Hippel-Lindau gene (VHL) leads to upregulation of hypoxia inducible factor-1a (HIF1a), a transcription factor that mediates cellular responses to hypoxia. This defect in the oxygen-sensing pathway causes increased expression of a broad range of hypoxia-regulated genes. Clinically, Chuvash polycythemia (CP) patients display not only erythrocytosis, but also premature mortality related to cerebrovascular and peripheral thrombotic events. As it is not clear that the thrombophilic nature of CP correlates with elevated hematocrit (Gordeuk et al, Blood103: 3924, 2004), we postulated that homocysteine may be a contributive factor, as preliminary data suggests that CP homozygotes have elevated plasma homocysteine levels (Sergueva, in preparation). Levels of homocysteine depend on its synthesis, involving S-adenosylmethionine, and its metabolism, either via remethylation to methionine, involving methylenetetrahydrofolate reductase (MTHFR), or via degradation by transsulfuration, involving cystathionine beta-synthase (CBS). Severe MTHFR and CBS deficiencies due to rare homozygous mutations lead to extremely high levels of serum homocysteine and are characterized clinically by a high incidence of thromboembolic complications, in addition to a wide range of other clinical symptoms. A recent microarray analysis that looked at the regulation of gene transcription by HIF-1a revealed that CBS and MTHFR gene expressions appear to be down regulated by hypoxia in endothelial cells (Manalo et al, Blood 105: 659, 2005). Downregulation of the genes responsible for homocysteine metabolism may therefore explain the elevated plasma homocysteine concentrations in CP. As hypoxia-regulated genes are often cell-type specific, we studied several types of easily accessible cells and detected expression of CBS and MTHFR in platelets, granulocytes, and EBV-immortalized lymphocytes in normal controls. In order to quantitate this expression, we used real-time RT-PCR and found no quantitative difference between EBV-immortalized lymphocytes in 4 homozygous CP patients, 3 heterozygote CP patients and 1 control. We then examined the peripheral blood from one CP patient and three controls. Although the numbers were small, the CP granulocytes and platelets showed decreased expression of MTHFR compared to controls, with decreased CBS expression seen in the CP granulocytes. These results suggest that the upregulation of HIF1a seen in CP patients might lead to decreased metabolism of homocysteine, which in turn, might contribute to the increased thromboembolic risk seen in CP. As these findings will need to be confirmed with a larger number of patients, we are currently in the process of collecting all accessible CP samples from the U.S. and from Chuvashia and the Italian island of Ischia (Perrotta et al, Blood 107: 514, 2006). Using the peripheral blood cells and in vitro expanded endothelial cells from these patients (Ingram et al, Blood104:2752, 2004), we hope to analyze the transcripts and enzyme activity of the genes involved in homocysteine synthesis and metabolism and to correlate these findings with CP plasma homocysteine levels.
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.
