DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for corneal degeneration — screening already-approved drugs against its 16-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCorneal degeneration maps to a 16-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 corneal degeneration 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
protein tyrosine phosphatase receptor type B (PTPRB) — PTPRB 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 tert-butoxycarbonyldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2I4G · 1.65 Å · ligand N-(TERT-BUTOXYCARBONYL)-L-TYROSYL-N-METHYL-4-(SULFOAMINO)-L-PHENYLALANINAMIDE (UA1). Experimental structure, not a prediction.
What the evidence adds up to
Whole-exome sequencing of 11 multiplex keratoconus families of European ancestry identified 23 rare heterozygous potentially pathogenic variants in eight genes, with nonsynonymous substitutions in HSPG2, EML6 and CENPF in two families each and in NBEAL2, LRP1B, PIK3CG and MRGPRD in three families each; ITGAX carried substitutions in two families and a nonsense allele in a third. Transcript and protein for most genes were detected in cornea and corneal stromal cultures, and siRNA inhibition of HSPG2, EML6, NBEAL2 and CENPF upregulated COL1A1, indicating a functional link to stromal matrix production. Serum ITGAX was elevated in affected members of three families compared with ten unrelated controls. These data implicate cytoskeletal, secretory granule and extracellular matrix genes in keratoconus but provide no therapeutic intervention.
A 20-year-old patient with superior pellucid marginal corneal degeneration and acute hydrops from Descemet's membrane rupture underwent perforating/lamellar corneo-scleroplasty. Seventeen years postoperatively the graft remained nearly clear, best corrected visual acuity was 0.8, central corneal thickness 540 microm, endothelial cell count 1250/mm2, with regular central astigmatism, no anterior synechia and no recurrence or progression. The contralateral eye showed no corneal changes. This single case demonstrates long-term stability after surgical reconstruction, not a pharmacological effect.
A novel C-terminal Gsdma3 mutation in mice caused degeneration of sebaceous glands, complete loss of pelage, and degeneration of Meibomian glands; corneal inflammation with neovascularisation appeared in half of affected older mice, mainly after six months, coinciding with Meibomian gland degeneration and suggesting altered tear-film composition as the cause. A 2016 Russian report claims Visomitin eye drops have high therapeutic efficacy and safety in primary and secondary corneal dystrophies, but provides no comparative data, sample sizes or objective outcome measures. A 2023 review notes corneal lesions remain a public health problem with costly and uncertain treatment responses, and another 2023 review states low effectiveness of therapeutic treatment, donor shortages and rejection reactions after transplantation prompt searches for more effective methods, including allogenic stem cells, without presenting clinical results.
The genetics of corneal dystrophies shows both genetic heterogeneity, as in Meesmann dystrophy caused by keratins 3 and 12, and phenotypic diversity, with keratoepithelin mutations causing several distinct dystrophies; a molecular classification was proposed in 1999. Corneal degenerations, unlike dystrophies, are not inherited, arise from age, systemic disease, local inflammation or chronic toxic exposure, and treatment should address the primary disease before corneal changes. What remains missing is any randomised controlled trial of a drug for corneal degeneration, a validated biomarker to stratify patients by genetic or inflammatory subtype, and long-term safety data for the stem cell or eye drop approaches mentioned only in reviews and single-centre reports.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Human Molecular Genetics · 2021 · 30 citations · open access
Pathogenic alleles in microtubule, secretory granule and extracellular matrix-related genes in familial keratoconus
AbstractKeratoconus is a common corneal defect with a complex genetic basis. By whole exome sequencing of affected members from 11 multiplex families of European ancestry, we identified 23 rare, heterozygous, potentially pathogenic variants in 8 genes. These include nonsynonymous single amino acid substitutions in HSPG2, EML6 and CENPF in two families each, and in NBEAL2, LRP1B, PIK3CG and MRGPRD in three families each; ITGAX had nonsynonymous single amino acid substitutions in two families and an indel with a base substitution producing a nonsense allele in the third family. Only HSPG2, EML6 and CENPF have been associated with ocular phenotypes previously. With the exception of MRGPRD and ITGAX, we detected the transcript and encoded protein of the remaining genes in the cornea and corneal cell cultures. Cultured stromal cells showed cytoplasmic punctate staining of NBEAL2, staining of the fibrillar cytoskeletal network by EML6, while CENPF localized to the basal body of primary cilia. We inhibited the expression of HSPG2, EML6, NBEAL2 and CENPF in stromal cell cultures and assayed for the expression of COL1A1 as a readout of corneal matrix production. An upregulation in COL1A1 after siRNA inhibition indicated their functional link to stromal cell biology. For ITGAX, encoding a leukocyte integrin, we assayed its level in the sera of 3 affected families compared with 10 unrelated controls to detect an increase in all affecteds. Our study identified genes that regulate the cytoskeleton, protein trafficking and secretion, barrier tissue function and response to injury and inflammation, as being relevant to keratoconus.
Current Opinion in Ophthalmology · 1999 · 26 citations
A new clinical perspective of corneal dystrophies through molecular genetics
AbstractIn the past 2 years, significant advances have been made in the genetics of corneal dystrophies. Genetic heterogeneity (one disease condition caused by single mutations in any one of multiple genes) and phenotypic diversity (many disease conditions caused by mutations in a single gene) are common emerging themes. Genetic heterogeneity in Meesmann corneal dystrophy was established with the identification of two causative genes, keratins 3 and 12, that encode cytoskeletal proteins. Conversely, mutations in a single gene, keratoepithelin, were found to cause several distinct corneal dystrophies affecting the Bowman layer and the stroma. We present a novel preliminary classification of corneal dystrophies based on molecular etiology. This classification may be useful in understanding the pathogenesis of corneal dystrophies and in developing new strategies to treat these dystrophies.
Russian Annals of Ophthalmology · 2018 · 9 citations
Corneal degenerations
AbstractDegeneration is the process of change occurring in cells, their parts or intracellular matter that happens due to external factors affecting the life of an organism and results in gradual disruption of normal condition of the tissue or the organ, and possibly complete loss of its functionality. Corneal degenerations may be caused by age-related physiological changes, associated with a certain systemic disease or local inflammations, or be the consequence of chronic toxic action of unhealthy environmental factors on the eye. Unlike dystrophies, corneal degenerations cannot be inherited and do not onset early. When corneal degenerations significantly affect visual acuity, the treatment should aim at alleviating the primary disease before inducing changes in the cornea. The existence of such pathology is important to remember and timely differentiate from acute inflammatory processes of various etiology that require immediate treatment. The right diagnosis is the key factor in choosing effective treatment strategy and thus achieving positive clinical results.
Klinische Monatsblätter für Augenheilkunde · 2003 · 3 citations
Langzeitergebnisse nach perforierender Korneoskleralplastik bei akuter unilateraler superiorer pelluzider marginaler Hornhautdegeneration
AbstractPURPOSE: This case report shows the long-term results after perforating corneo-scleroplasty in a rare case of superior pellucid marginal corneal degeneration with acute hydrops due to rupture of Descemet's membrane. PATIENT: In the left cornea of a 20-year-old patient with peripheral stromal thinning from 9 to 3 o'clock a rupture in Descemet's membrane occurred followed by lamellar splitting of the mid-stromal region. Due to the decrease in visual acuity and pain from corneal edema a surgical treatment was performed consisting of a perforating/lamellar corneo-scleroplasty protecting the anterior chamber angle. RESULTS: The status has remained stable for 17 years after surgery with nearly clear graft, best corrected visual acuity of 0.8 and no signs of recurrence or progression of the disease. Central astigmatism is regular, the endothelial cell count is 1250/mm2 in the central cornea, the central corneal thickness is 540 microm and only a mild vascularised superficial pannus and slight opacities in the predescemetal layer of the graft are found. There are no anterior synechia. On the right eye visual acuity is 0.8 due to slight amblyopia. There are no corneal changes which would indicate bilaterality of the disease. CONCLUSIONS: Our findings must be interpreted as an atypically localised superior pellucid marginal corneal degeneration with rupture of Descemet's membrane followed by acute corneal hydrops. When reduction of visual acuity or pain occurs a surgical treatment by perforating/lamellar corneo-scleroplasty can be performed stopping the progression of the disease and achieving a stable optical rehabilitation and absence of pain even after decades.
A Novel C-Terminal Mutation in <i>Gsdma3</i> (C+/H−) Leads to Alopecia and Corneal Inflammatory Response in Mice
AbstractPurpose: Mutations in the gene encoding Gasdermin A3 (Gsdma3) have been described to cause severe skin phenotypes, including loss of sebaceous glands and alopecia, in mice. We discovered a novel C-terminal mutation in Gsdma3 in a new mouse line and characterized a less frequently reported corneal phenotype, likely caused by degeneration of Meibomian glands of the inner eyelid. Methods: We used histologic methods to evaluate the effects of the C+/H- mutation on sebaceous gland and skin morphology as well as Meibomian glands of the inner eyelid and corneal tissue. Chromosomal aberrations were excluded by karyogram analyses. The mutation was identified by Sanger sequencing of candidate genes. Results: Analyses of skin samples from affected mice confirmed the frequently reported phenotypes associated with mutations in Gsdma3: Degeneration of sebaceous glands and complete loss of pelage. Immunologic staining of corneal samples suggested an inflammatory response with signs of neovascularization in half of the affected older mice. While the corneal phenotype was observed at irregular time points, mainly after 6 months, its appearance coincided with a degeneration of Meibomian glands in the eyelids of affected animals. Conclusions: The mutation described herein is associated with inflammation and neovascularization of corneal tissue. Simultaneous degeneration of Meibomian glands in affected animals suggested a change in tear-film composition as the underlying cause for the corneal phenotype. Our data further support that different pathogenic mechanisms underlie some of the reported mutations in Gsdma3.
Meditsinskiy sovet = Medical Council · 2016 · 1 citations · open access
Questions of treatment of degenerative changes in the anterior chamber of the eye
AbstractDegenerative corneal diseases represent a relevant issue in the present-day ophthalmology. The key areas in the treatment of degenerative changes in the anterior chamber of the eye are anti-inflammatory, keratoprotective and tear substitute therapies. Visomitin eye drops have high therapeutic efficacy and safety of use in the treatment of primary and secondary corneal dystrophies.
Revista de la Facultad de Medicina Humana · 2023 · 0 citations · open access
Important advances in regenerative medicine. A vision to the future of ophthalmology
AbstractThe treatment of corneal lesions continues to be a topic of great interest. However, despite the development of new technologies and due to the slow evolution and uncertain healing of corneal lesions, they still represent a public health problem since patients can be affected for life, affecting the family and the health system due to the costly and uncertain response to treatment. For this reason, the need arises to seek therapeutic alternatives to treat these patients.
EPRA International Journal of Multidisciplinary Research (IJMR) · 2023 · 0 citations · open access
REPAIR CAPABILITIES OF ALLOGENIC STEM CELLS IN DISEASES OF THE ANTERIOR SEGMENT OF THE EYEBALL
AbstractCorneal diseases are one of the leading causes of low vision and blindness throughout the world, which serves to increase visual disability among the young and working-age population. The low effectiveness of therapeutic treatment, lack of donor material and frequent rejection reactions after transplantation prompt the search for more effective methods of treating corneal diseases, both inflammatory and dystrophic.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works using Disease Ontology synonyms, 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.
