DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Brugada syndrome — screening already-approved drugs against its 38-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleBrugada syndrome maps to a 38-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 brugada syndrome 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
HD domain containing 2 (HDDC2) — HDDC2 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 2-{2-[2-(2-ethoxy-ethoxydrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4L1J · 1.824 Å · ligand 2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL (PE4). Experimental structure, not a prediction.
What the evidence adds up to
In 2008, transcriptional profiling of right-ventricular endomyocardial biopsies from 10 unrelated Brugada probands, 11 non-diseased organ-donors, seven heart-transplant recipients, 10 with arrhythmogenic right-ventricular cardiomyopathy, and nine with idiopathic right-ventricular outflow-tract tachycardia found that Brugada patients showed distinct clustering differences versus the two control and two other ventricular-tachyarrhythmia groups. Among 77 genes encoding ion-channel or ion-transporter subunits, 14 were differentially expressed. Nav1.5 and the potassium channels Kv4.3 and Kir3.4 were more weakly expressed, while the sodium channel Nav2.1 and the potassium channel TWIK1 were more strongly expressed, in Brugada syndrome. Differences were also seen in calcium-homeostasis transcripts, including stronger expression of RYR2 and NCX1. The molecular profile of Brugada patients with SCN5A mutations did not differ from Brugada patients without SCN5A mutations.
By 2010, the genetic basis of Brugada syndrome remained limited. Since the first genetic defect was discovered in 1998, several genes had been identified, but together they explained only 30% of cases. New polymorphisms, mutations, and genes were being described, but the review concluded that knowledge of the genetic determinants remained limited.
A 2013 study of a Spanish family clinically diagnosed with Brugada syndrome identified a nonsense variation (p.E61X) in the RANGRF gene in the index case and five other family members. All six showed a normal electrocardiogram at baseline. Flecainide test unmasked a type 1 Brugada syndrome electrocardiogram in only two of the relatives. The authors suggested that p.E61X_RANGRF is a rare genetic variation with an uncertain role in Brugada syndrome and that further studies must be performed to elucidate its potential pathogenic role.
A 2019 review noted that more than three decades after its initial description in 1993, Brugada syndrome remains engulfed in controversy. The main challenges include the diagnostic pathway and criteria, risk stratification of asymptomatic patients, and pharmacological and interventional risk modification strategies. What is still missing is a clear pathophysiological understanding of the disease, reliable stratification of asymptomatic patients, and evidence from adequately funded trials to settle the controversies around diagnosis and treatment.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
European Heart Journal · 2008 · 57 citations · open access
Transcriptional profiling of ion channel genes in Brugada syndrome and other right ventricular arrhythmogenic diseases
AbstractAIMS: Brugada syndrome is an inherited sudden-death arrhythmia syndrome. Na(+)-current dysfunction is central, but mutations in the SCN5A gene (encoding the cardiac Na(+)-channel Nav1.5) are present in only 20% of probands. This study addressed the possibility that Brugada patients display specific expression patterns for ion-channels regulating cardiac conduction, excitability, and repolarization. METHODS AND RESULTS: Transcriptional profiling was performed on right-ventricular endomyocardial biopsies from 10 unrelated Brugada probands, 11 non-diseased organ-donors, seven heart-transplant recipients, 10 with arrhythmogenic right-ventricular cardiomyopathy, and nine with idiopathic right-ventricular outflow-tract tachycardia. Brugada patients showed distinct clustering differences vs. the two control and two other ventricular-tachyarrhythmia groups, including 14 of 77 genes encoding important ion-channel/ion-transporter subunits. Nav1.5 and K(+)-channels Kv4.3 and Kir3.4 were more weakly expressed, whereas the Na(+)-channel Nav2.1 and the K(+)-channel TWIK1 were more strongly expressed, in Brugada syndrome. Differences were also seen in Ca(2+)-homeostasis transcripts, including stronger expression of RYR2 and NCX1. The molecular profile of Brugada patients with SCN5A mutations did not differ from Brugada patients without SCN5A mutations. CONCLUSION: Brugada patients exhibit a common ion-channel molecular expression signature, irrespective of the culprit gene. This finding has potentially important implications for our understanding of the pathophysiology of Brugada syndrome, with possible therapeutic and diagnostic consequences.
Current Opinion in Cardiology · 2010 · 38 citations
Genetics of Brugada syndrome
AbstractPURPOSE OF REVIEW: The Brugada syndrome has been investigated in depth since its description in 1992 both on a clinical and on a basic research level. Since the discovery of the first genetic defect in 1998, several genes have been subsequently identified. However, to date all these genes together explain only 30% of the cases, indicating that there is still an important amount of work to be done to totally unravel the genetic basis of this lethal disease. In the present study, we will focus on recent achievements in the genetic basis of this disease. RECENT FINDINGS: In 2009, several additional genetic mutations have been associated with the disease. Additionally, a common variant has been described as a genetic modulator of Brugada syndrome among carriers of a SCN5A mutation. SUMMARY: The number of scientific publications dealing with the syndrome has continued to increase substantially in recent years. New polymorphisms, mutations and genes associated with the disease have been described. However, despite the advances, knowledge of the genetic determinants of the Brugada syndrome remains limited.
Cardiology Journal · 2013 · 17 citations · open access
Brugada syndrome and p.E61X_RANGRF
AbstractBACKGROUND: Brugada syndrome is an inherited cardiac condition transmitted with an autosomal dominant pattern which can lead to sudden cardiac death from malignant ventricular arrhythmias. The RANGRF gene has recently been proposed to be associated with Brugada syndrome. This gene encodes the MOG1 protein, a co-factor required for the full functioning of the cardiac sodium channel Nav1.5. The nonsense p.E61X genetic variation in the RANGRF gene has been postulated as responsible for Brugada syndrome although no clear association has been established. METHODS: We clinically and genetically evaluated a Spanish family diagnosed with Brugada syndrome. A comprehensive genetic analysis of all genes to date responsible for Brugada syndrome was performed in the index case. RESULTS: The index case was clinically diagnosed with Brugada syndrome after flecainide test. We identified a nonsense variation (p.E61X) in the index case and in other five family members. All of them showed a normal electrocardiogram in basal conditions. Flecainide test unmasked a type 1 Brugada syndrome electrocardiogram only in two of the relatives. CONCLUSIONS: We suggest that p.E61X_RANGRF is a rare genetic variation with an uncertain role in Brugada Syndrome. Further studies must be performed to elucidate the potential pathogenic role of p.E61X_RANGRF in Brugada Syndrome.
European Cardiology Review · 2019 · 12 citations · open access
Current Controversies and Challenges in Brugada Syndrome
AbstractMore than three decades since its initial description in 1993, Brugada syndrome remains engulfed in controversy. This review aims to shed light on the main challenges surrounding the diagnostic pathway and criteria, risk stratification of asymptomatic patients, pharmacological and interventional risk modification strategies as well as our current pathophysiological understanding of the disease.
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.
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