DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Axenfeld-Rieger syndrome type 1 — 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 moduleAxenfeld-Rieger syndrome type 1 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 axenfeld-rieger syndrome type 1 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
PR/SET domain 5 (PRDM5) — PRDM5 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6XAZ · 1.7 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Axenfeld-Rieger syndrome type 1 is an autosomal dominant disorder with variable clinical expression. The main causative gene is PITX2 at 4q25, but mutations in FOXC1 also produce overlapping phenotypes. In two unrelated patients diagnosed with Rieger syndrome, cytogenetically invisible submicroscopic deletions at 4q25 were found; one carried a t(4;17)(q25;q22)dn translocation with a deletion at the 4q breakpoint, the other an interstitial deletion of 4q25. Both deletions included only PITX2 and ENPEP. A novel PITX2 mutation (c.300_301delinsT) was identified in two Korean patients from one family, expanding the known mutation spectrum.
A novel L130F missense mutation in FOXC1 was found in two patients with Axenfeld-Rieger syndrome. The mutant protein was expressed at levels similar to wild-type but migrated at an apparent reduced molecular weight, suggesting differential phosphorylation. The L130F protein had a significantly impaired capacity to localise to the nucleus, bind DNA, and transactivate reporter genes. This demonstrates that helix 3 of the forkhead domain is critical for FOXC1 nuclear localisation, DNA binding, and gene activation.
In a Korean family with five affected members across three generations, clinical findings included iris hypoplasia, iridocorneal adhesions, posterior embryotoxon, and advanced glaucoma. None had systemic anomalies. Two FOXC1 mutations (c.1362_1364insCGG and c.1142_1144insGGC) were identified in four affected members. No quantitative data on visual outcomes, glaucoma progression rates, or treatment responses were reported in any of these studies.
What is still missing is prospective natural history data with standardised ophthalmologic endpoints, larger cohorts to establish genotype-phenotype correlations, and any clinical trial testing a therapeutic intervention. No drug treatment was studied or proposed 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.
AbstractAxenfeld-Rieger syndrome (ARS) is a genetically heterogeneous autosomal dominant disorder mainly characterized by developmental defects of the anterior segment and extraocular anomalies. ARS shows great clinical variability and encompasses several conditions with overlapping phenotypes, including Rieger syndrome (RS). RS is characterized by developmental defects of the eyes, teeth and umbilicus, and the main causative gene is PITX2 (paired-like homeodomain transcription factor 2, or RIEG1) at 4q25. PITX2 mutations show great variety, from point mutations to microscopic or submicroscopic deletions, and apparently balanced translocations in few cases. We identified cytogenetically undetectable submicroscopic deletions at 4q25 in two unrelated patients diagnosed with RS. One patient had a t(4;17)(q25;q22)dn translocation with a deletion at the 4q breakpoint, and the other patient had an interstitial deletion of 4q25. Both deletions included only the PITX2 and ENPEP (glutamyl aminopeptidase) genes.
Analyses of a Novel L130F Missense Mutation in FOXC1
AbstractOBJECTIVE: To understand how the novel L130F mutation, found in 2 patients with Axenfeld-Rieger syndrome, disrupts function of the forkhead box C1 protein (FOXC1). METHODS: Sequencing DNA from patients with Axenfeld-Rieger syndrome identified a novel missense mutation that results in an L130F substitution in the FOXC1 gene. Site-directed mutagenesis was used to introduce the L130F mutation into the FOXC1 complementary DNA. The level of L130F protein expression was determined by means of immunoblotting. We determined the mutant protein's ability to localize to the nucleus, bind DNA, and transactivate a reporter construct. RESULTS: The FOXC1 L130F mutant protein is expressed at levels similar to those of wild-type FOXC1. The L130F protein, however, migrated at an apparent reduced molecular weight compared with the wild-type protein, suggesting that the mutant and wild-type proteins may be differentially phosphorylated. The L130F protein also had a significantly impaired capacity to localize to the nucleus, bind DNA, and transactivate reporter genes. CONCLUSIONS: The disease-causing L130F mutation further demonstrates that helix 3 of the forkhead domain is important for the FOXC1 protein to properly localize to the nucleus, bind DNA, and activate gene expression. CLINICAL RELEVANCE: The inability of FOXC1 to function owing to the L130F mutation provides further insight into how disruptions in the FOXC1 gene lead to human Axenfeld-Rieger syndrome.
Korean Journal of Ophthalmology · 2015 · 9 citations · open access
A Family with Axenfeld-Rieger Syndrome: Report of the Clinical and Genetic Findings
AbstractPURPOSE: To describe clinical findings in a Korean family with Axenfeld-Rieger syndrome. METHODS: A retrospective review of clinical data about patients with diagnosed Axenfeld-Rieger syndrome. Five affected members of the family underwent a complete ophthalmologic examination. We screened the forkhead box C1 gene and the pituitary homeobox 2 gene in patients. Peripheral blood leukocytes and buccal mucosal epithelial cells were obtained from seven members of a family with Axenfeld-Rieger syndrome. DNA was extracted and amplified by polymerase chain reaction, followed by direct sequencing. RESULTS: The affected members showed iris hypoplasia, iridocorneal adhesions, posterior embryotoxon, and advanced glaucoma in three generation. None had systemic anomalies. Two mutations including c.1362_1364insCGG and c.1142_1144insGGC were identified in forkhead box C1 in four affected family members. CONCLUSIONS: This study may help to understand clinical findings and prognosis for patients with Axenfeld-Rieger syndrome.
Annals of Laboratory Medicine · 2013 · 7 citations · open access
Novel c.300_301delinsT Mutation in <i>PITX2</i> in a Korean Family with Axenfeld-Rieger Syndrome
AbstractAxenfeld-Rieger syndrome (ARS) is characterized by anomalies of the anterior segment of the eye and systemic abnormalities. Mutations in the FOXC1 and PITX2 genes are underlying causes of ARS, but there has been few reports on genetically confirmed ARS in Korea. We identified a novel PITX2 mutation (c.300_301delinsT) in 2 Korean patients from a family with ARS. We expand the spectrum of PITX2 mutations and, to the best of our knowledge, this is the first confirmed family of PITX2-related ARS in Korea.
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.
