DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Fuchs' endothelial dystrophy — screening already-approved drugs against its 26-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleFuchs' endothelial dystrophy maps to a 26-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 fuchs' endothelial dystrophy 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
ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 3 (ST8SIA3) — ST8SIA3 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 ctpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5BO7 · 1.85 Å · ligand CYTIDINE-5'-TRIPHOSPHATE (CTP). Experimental structure, not a prediction.
What the evidence adds up to
In 21 corneal buttons from Fuchs dystrophy patients and 15 control corneas, DNA fragmentation was seen in the epithelium, stroma, and endothelium of 6 out of 7 Fuchs corneas. A statistically significant difference was found in the expression of Bax and its mRNA in the stroma, but not in the endothelium, of Fuchs corneas. When keratocytes from Fuchs patients were exposed to the apoptotic inducer camptothecin, they responded with increased Bax and low Bcl-2, a pattern distinct from normal keratocytes. The authors concluded that excessive apoptosis may be an important mechanism in the pathogenesis of Fuchs dystrophy.
Reported clearance rates following Descemet’s stripping only (DSO) range from 63 to 100% in recent series, with variation between surgical techniques. Topical Rho-kinase inhibitor has been reported as successfully salvaging failing cases, and its use as an adjuvant is gaining widespread adoption, though the results of early series are only now arriving. Patient characteristics that determine success, apart from a phenotype of central guttata with clear periphery, remain elusive. The addition of Rho-associated kinase inhibitor appears to improve predictability, but further results must be published and scrutinised.
In a retrospective case-control study of 430 eyes from 215 patients with endothelial dystrophy, the relative risk of primary open-angle glaucoma in white, African American, and Hispanic patients was 0.94, 2.59, and 3.7, respectively, none reaching statistical significance. The relative risk of secondary glaucoma and combined ocular hypertension or secondary glaucoma was significantly higher after penetrating keratoplasty than after Descemet stripping endothelial keratoplasty (4.15 and 1.95, respectively). No increased risk of primary open-angle glaucoma was found in patients with endothelial dystrophy.
Proteomic analysis of Descemet’s membrane and endothelial layer from Fuchs patients and controls identified 26 differentially regulated proteins, 6 of which were regulated in both of two quantitation methods. The level of type VIII collagen was unaltered, even though that protein has been implicated in familial early-onset forms of the disease. Many of the differentially regulated proteins are extracellular proteins involved in proper assembly of the basement membrane in other tissues. The results support that the morphological changes in Fuchs dystrophy are caused in part by an aberrant assembly of the extracellular matrix within the Descemet’s membrane and endothelial layer. What remains missing is a clear patient stratification for DSO success, prospective validation of Rho-kinase inhibitor as an adjuvant, and any drug treatment that targets the apoptotic or extracellular matrix disorder directly.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Archives of Ophthalmology · 2001 · 132 citations
The Role of Apoptosis in the Pathogenesis of Fuchs Endothelial Dystrophy of the Cornea
AbstractOBJECTIVE: To investigate the potential role of apoptosis in the pathogenesis of Fuchs endothelial dystrophy of the cornea. METHODS: Twenty-one corneal buttons from patients with Fuchs dystrophy and 15 control corneas were studied. Apoptosis was assessed by the in situ end-labeling of double-stranded DNA breaks, and by immunohistochemical characterization of cellular markers associated with apoptosis (Fas, FasL, Bcl-2, and Bax). Expression of Bcl-2 and Bax mRNA in the corneal stroma and endothelium was separately analyzed by a semiquantitative reverse transcriptase polymerase chain reaction. Furthermore, cultivated keratocytes generated from diseased corneal buttons and donor rims were exposed to camptothecin, an apoptotic inducer, for 6 and 24 hours. They were then examined for protein and messenger RNA (mRNA) expression of apoptotic regulatory molecules. RESULTS: DNA fragmentation was seen in the epithelium, stroma, and endothelium in 6 of 7 corneas with Fuchs dystrophy. A statistically significant difference was identified in the expression of Bax and its mRNA in the stroma, but not in the endothelium of Fuchs dystrophy corneas. Following exposure to camptothecin, keratocytes from patients with Fuchs dystrophy responded with an increased level of Bax and a low level of Bcl-2. This trend was distinctively different from the response of normal keratocytes. CONCLUSIONS: The evidence in this study points to a disease-related disturbance in the regulation of apoptosis in Fuchs dystrophy. Our findings suggest that excessive apoptosis may be an important mechanism in the pathogenesis of Fuchs dystrophy.
Current Opinion in Ophthalmology · 2019 · 96 citations
Descemet's stripping without endothelial keratoplasty
AbstractPURPOSE OF REVIEW: To summarize the recent literature regarding descemetorhexis stripping without endothelial keratoplasty (DWEK), increasingly referred to as Descemet's stripping only (DSO). To report the characteristic clinical, confocal and histologic findings associated with this procedure. RECENT FINDINGS: Reported clearance rates following DSO range from 63 to 100% in recent series, with variation between surgical techniques. Topical Rho-kinase inhibitor has been reported as successfully salvaging failing cases. Its use as an adjuvant to the surgery is gaining widespread adoption with the results of early series now arriving. Apart from a phenotype of central guttata with clear periphery, patient characteristics which determine success remain elusive. Surgical factors affecting success are increasingly well understood, with stromal injury felt to be a retardant to healing. Characteristic clinical signs have been observed and are described herein. Clinical, confocal and light microscopic images are obtained from patients in clinical trials of DSO with ripasudil. SUMMARY: DSO is gaining acceptance as a surgical option for a subset of patients with Fuchs' Dystrophy. The addition of Rho-associated kinase inhibitor appears to improve predictability but further results to this effect must be published and scrutinized.
Glaucoma in Patients With Corneal Endothelial Dystrophy
AbstractOBJECTIVES: The prevalence of primary open-angle glaucoma (POAG) in patients with corneal endothelial dystrophy has not been previously studied. Prevalence of POAG in patients with endothelial dystrophy was compared with that in the general population to determine the presence of a relationship between the diseases. DESIGN: Retrospective case-control study. METHODS: A study of the prevalence of POAG in 430 eyes of 215 patients with endothelial dystrophy was conducted. Patients followed for less than 6 months were excluded. Relative risk of POAG was calculated using age- and race-matched control data from the Baltimore Eye Survey and the Los Angeles Latino Eye Survey for comparison. Ocular hypertension (OHT) and secondary glaucoma (SG) rates after penetrating keratoplasty (PK) and Descemet stripping endothelial keratoplasty (DSEK) were separately analyzed. RESULTS: Relative risk of POAG in white, African American, and Hispanic patients with endothelial dystrophy was 0.94, 2.59, and 3.7, respectively (P = 0.89, 95% confidence interval [CI], -0.028 to 0.0289; P = 0.13; 95% CI, 0.011-0.274; P = 0.055; 95% CI, 0.0423-0.356). Relative risk of SG and combined OHT/SG in PK versus DSEK was 4.15 and 1.95 (P < 0.001; 95% CI, 0.0654-0.322; P = 0.005; 95% CI, 0.116-0.332), respectively. No differences in OHT/SG rates were found comparing PK-triple with PK, DSEK-triple with DSEK, and repeat with primary PK or DSEK (P = 0.98; P = 0.62; P = 0.95; P = 0.87), respectively. CONCLUSIONS: No increased risk of POAG was found in patients with endothelial dystrophy. Increased prevalence of OHT/SG was shown with PK versus DSEK; possible mechanisms include mechanical closure of Schlemm's canal by running suture and prolonged steroid use.
INDIGO (University of Illinois at Chicago) · 2015 · 0 citations · open access
Proteomics of Fuchs’\nEndothelial Corneal Dystrophy\nSupport That the Extracellular Matrix of Descemet’s Membrane\nIs Disordered
AbstractFuchs’\nendothelial corneal dystrophy (FECD) is a major corneal\ndisorder affecting the innermost part of the cornea, leading to visual\nimpairment. As the morphological changes in FECD are mainly observed\nin the extracellular matrix of the Descemet’s membrane/endothelial\nlayer, we determined the protein profiles of diseased and control\ntissues using two relative quantitation MS methods. The first quantitation\nmethod, based on the areas of the extracted ion chromatograms, quantified\nthe 51 and 48 most abundant proteins of the Descemet’s membrane/endothelial\nlayer in patient and control tissues, respectively, of which 10 were\nsignificantly regulated. The results indicated that the level of type\nVIII collagen was unaltered even though the protein previously has\nbeen shown to be implicated in familial early-onset forms of the disease.\nUsing the second relative quantitation method, iTRAQ, we identified\n22 differentially regulated proteins, many of which are extracellular\nproteins known to be involved in proper assembly of the basement membrane\nin other tissues. In total, 26 differentially regulated proteins were\nidentified, of which 6 proteins were regulated in both methods. These\nresults support that the morphological changes observed in FECD are\ncaused in part by an aberrant assembly of the extracellular matrix\nwithin the Descemet’s membrane/endothelial layer.
INDIGO (University of Illinois at Chicago) · 2015 · 0 citations · open access
Proteomics of Fuchs’\nEndothelial Corneal Dystrophy\nSupport That the Extracellular Matrix of Descemet’s Membrane\nIs Disordered
AbstractFuchs’\nendothelial corneal dystrophy (FECD) is a major corneal\ndisorder affecting the innermost part of the cornea, leading to visual\nimpairment. As the morphological changes in FECD are mainly observed\nin the extracellular matrix of the Descemet’s membrane/endothelial\nlayer, we determined the protein profiles of diseased and control\ntissues using two relative quantitation MS methods. The first quantitation\nmethod, based on the areas of the extracted ion chromatograms, quantified\nthe 51 and 48 most abundant proteins of the Descemet’s membrane/endothelial\nlayer in patient and control tissues, respectively, of which 10 were\nsignificantly regulated. The results indicated that the level of type\nVIII collagen was unaltered even though the protein previously has\nbeen shown to be implicated in familial early-onset forms of the disease.\nUsing the second relative quantitation method, iTRAQ, we identified\n22 differentially regulated proteins, many of which are extracellular\nproteins known to be involved in proper assembly of the basement membrane\nin other tissues. In total, 26 differentially regulated proteins were\nidentified, of which 6 proteins were regulated in both methods. These\nresults support that the morphological changes observed in FECD are\ncaused in part by an aberrant assembly of the extracellular matrix\nwithin the Descemet’s membrane/endothelial layer.
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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