DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for overhydrated hereditary stomatocytosis — 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 moduleOverhydrated hereditary stomatocytosis 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 overhydrated hereditary stomatocytosis 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
Rh associated glycoprotein (RHAG) — RHAG 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 clrdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7UZQ · 2.17 Å · ligand CHOLESTEROL (CLR). Experimental structure, not a prediction.
What the evidence adds up to
In a 2013 study, exome sequencing of a large kindred mapped the disease gene for dehydrated hereditary stomatocytosis to PIEZO1, identifying 11 heterozygous missense mutations in 26 affected individuals across 7 families. The mutations R2456H and R2488Q were shown to increase mechanosensitive ion-channel activity in red cells and in Xenopus oocytes, consistent with the altered cation content seen in patient red cells. PIEZO1 expression was detected in red cell plasma membranes, and its mRNA and protein levels rose during in vitro erythroid differentiation. The study also suggested a first correlation between a PIEZO1 mutation and perinatal edema.
A 2018 cohort study of 123 hereditary stomatocytosis patients found that PIEZO1 was the most frequently mutated gene, accounting for 47% of pedigrees. Among 29 PIEZO1 patients analysed for genotype-phenotype correlation, those with mutations in the central pore domain were more severely affected than those with mutations in the nonpore domain (59.1% nonpore, 40.9% pore). Overall, the patients showed macrocytic mild anaemia. The authors concluded that severity is linked to pore properties and intracellular domain interactions, and that this stratification is useful for diagnosis, prognosis, and management.
A 1999 review noted that all hereditary stomatocytoses involve increased red cell membrane permeability to sodium and potassium, with stomatocytic morphology. Dehydrated hereditary stomatocytosis was described as more heterogeneous than previously thought, including kindreds with pseudohyperkalemia or perinatal edema. The cause of overhydrated hereditary stomatocytosis remained elusive despite the consistent absence of the protein stomatin. The review stressed that splenectomy conferred a marked risk for thrombosis in adult life in all cases where it had been performed, emphasising the need to distinguish these conditions from hereditary spherocytosis.
What is still missing is a clear understanding of the molecular defect in overhydrated hereditary stomatocytosis, prospective data on whether genotype-pore domain stratification reliably predicts clinical outcomes in larger, unselected populations, and any clinical trial testing a targeted intervention. No drug is mentioned in any of 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.
Blood · 2013 · 327 citations
Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1
AbstractAutosomal dominant dehydrated hereditary stomatocytosis (DHSt) usually presents as a compensated hemolytic anemia with macrocytosis and abnormally shaped red blood cells (RBCs). DHSt is part of a pleiotropic syndrome that may also exhibit pseudohyperkalemia and perinatal edema. We identified PIEZO1 as the disease gene for pleiotropic DHSt in a large kindred by exome sequencing analysis within the previously mapped 16q23-q24 interval. In 26 affected individuals among 7 multigenerational DHSt families with the pleiotropic syndrome, 11 heterozygous PIEZO1 missense mutations cosegregated with disease. PIEZO1 is expressed in the plasma membranes of RBCs and its messenger RNA, and protein levels increase during in vitro erythroid differentiation of CD34(+) cells. PIEZO1 is also expressed in liver and bone marrow during human and mouse development. We suggest for the first time a correlation between a PIEZO1 mutation and perinatal edema. DHSt patient red cells with the R2456H mutation exhibit increased ion-channel activity. Functional studies of PIEZO1 mutant R2488Q expressed in Xenopus oocytes demonstrated changes in ion-channel activity consistent with the altered cation content of DHSt patient red cells. Our findings provide direct evidence that R2456H and R2488Q mutations in PIEZO1 alter mechanosensitive channel regulation, leading to increased cation transport in erythroid cells.
American Journal of Hematology · 2018 · 61 citations · open access
Genotype‐phenotype correlation and risk stratification in a cohort of 123 hereditary stomatocytosis patients
AbstractHereditary stomatocytoses (HSts) are a wide spectrum of hemolytic anemias in which the erythrocyte membrane cation permeability is increased. Dehydrated hereditary stomatocytosis is the most frequent among HSts. It is caused by missense mutations in PIEZO1 and KCNN4 genes. We described 123 patients enrolled in our Genetic Unit from 2013 to 2017. Overall HSt subjects exhibit macrocytic mild anemia. We found that PIEZO1 is the most frequent mutated gene within our families (47% of pedigrees). In 59.1% of cases the mutations localized in the nonpore protein domain, while in 40.9% of patients they localized in the central pore region. The genotype-phenotype correlation analysis on 29 PIEZO1-patients demonstrated that most of severely affected patients carried mutations in the pore domain, suggesting that the severity of this condition is related to the pore properties and intracellular domain that could be responsible of interactions with intracellular components. This is the first cohort study on a large set of hereditary stomatocytosis patients, stratified according to their causative gene useful for diagnosis, prognosis, and management of these patients.
Current Opinion in Hematology · 1999 · 58 citations
Hereditary dehydrated and overhydrated stomatocytosis: recent advances
AbstractThe hereditary stomatocytoses and allied disorders are genetic defects of the erythrocyte membrane that result in abnormal permeability to the univalent cations Na+ and K+. Although rare, these conditions reflect abnormalities in physiologic mechanisms that are of paramount interest. All cases (as defined here) show increased plasma membrane permeability to Na+ and K+ and, to a greater or lesser degree, stomatocytic morphology. Dehydrated hereditary stomatocytosis, the most common form of hereditary stomatocytosis, is more heterogeneous than previously thought and includes kindreds showing pseudohyperkalemia or perinatal edema, or both. The gene responsible for both dehydrated hereditary stomatocytosis and familial pseudohyperkalemia, a nonhemolytic variant that presents with high plasma K+ levels, has been mapped to 16q23-qter. The cause of overhydrated hereditary stomatocytosis remains elusive despite the manifest lack of the enigmatic protein stomatin in the erythrocyte membrane. In all cases where splenectomy has been performed, this procedure has conferred a marked risk for thrombosis in adult life. This finding stresses the importance of diagnostic distinction between these conditions and hereditary spherocytosis.
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.
