DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for macular degeneration — screening already-approved drugs against its 41-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleMacular degeneration maps to a 41-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 macular 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
kynureninase (KYNU) — KYNU 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 plpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3E9K · 1.7 Å · ligand PYRIDOXAL-5'-PHOSPHATE (PLP). Experimental structure, not a prediction.
What the evidence adds up to
A 2007 prospective nested case-control study of 457 AMD cases and 1071 matched controls found that participants with one or two copies of the CFH Y402H variant were, respectively, 1.98 and 3.92 times more likely to develop AMD; for the LOC387715 A69S variant the incidence rate ratios were 2.38 and 5.66. Subjects homozygous for both risk alleles had a 50-fold increased risk. Cigarette smoking and obesity multiplied those genetic risks. The fraction of AMD cases attributable to these two variants was 63%.
A 2010 study in albino rats exposed to 12 hours of 3000-lux cyclic light for up to six months showed progressive retinal degeneration. After one month there was loss of the outer segments and about two-thirds of the outer nuclear layer, plus subretinal pigment epithelium neovascularisation. After three months almost the entire outer nuclear layer was absent and choroidal neovascularisation had penetrated Bruch’s membrane. After six months there were multiple foci of choroidal neovascularisation, retinal pigment epithelial fibrous metaplasia, and connective tissue bands containing blood vessels extending into the retina. All exposed animals showed increased staining for 4-hydroxy-2-nonenal and nitrotyrosine.
A 2020 study tested lamivudine (3TC), a nucleoside analogue reverse transcriptase inhibitor, against Alu RNA-induced retinal pigment epithelium degeneration. In cultured human RPE cells and in vivo mouse RPE cells transfected with Alu RNA, 3TC markedly reduced expression of IL-18 and IL-1β compared with a negative control. Alu RNA-induced expression of the senescence marker p16INK4a was also suppressed by 3TC in human RPE cells. The authors concluded that Alu RNA accumulation contributes to RPE cell senescence and that this process can be suppressed by 3TC, but noted that further verification is needed.
A 2007 review stated that before photodynamic therapy the only available treatment for neovascular AMD was laser photocoagulation, which could stabilise vision but was not enthusiastically received. Antivascular endothelial growth factor agents then allowed better visual outcomes than mere stabilisation. The review emphasised that there is still no cure. A 2011 review of dry AMD treatment confirmed that no drug is available for dry AMD, though some drug candidates had been identified and clinical end points for efficacy determination had been collected. What remains missing is a proven therapy for dry AMD, adequate clinical trial designs that can measure meaningful endpoints in a slowly progressive disease, and the funding to move candidate drugs through those trials.
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 · 2007 · 190 citations
A Prospective Study of 2 Major Age-Related Macular Degeneration Susceptibility Alleles and Interactions With Modifiable Risk Factors
AbstractOBJECTIVES: To delineate the magnitude of susceptibility to age-related macular degeneration (AMD) due to common variants in the gene for complement factor H (CFH) and the predicted gene LOC387715 and to determine whether these variants interact with modifiable risk factors. METHODS: We compared cases who developed AMD (n = 457) with 1071 age- and sex-matched control subjects in a prospective nested case-control study within the Nurses' Health Study and the Health Professionals Follow-up Study. We determined the incidence rate ratios and 95% confidence intervals (CIs) for AMD for each genotype and examined the interactions with modifiable risk factors. RESULTS: Participants with 1 or 2 copies of the Y402H variant of CFH were, respectively, 1.98 (95% CI, 1.64-2.40) and 3.92 (95% CI, 2.69-5.76) times more likely to develop AMD, whereas the incident rate ratios (95% CIs) for 1 and 2 copies of LOC387715 A69S were 2.38 (1.92-2.96) and 5.66 (3.69-8.76), respectively. The fraction of AMD cases attributable to these 2 variants was 63% (95% CI, 58%-68%). Subjects homozygous for both risk alleles had a 50-fold increased risk of AMD (95% CI, 10.8-237), and cigarette smoking and obesity multiplied the risks associated with these variants. CONCLUSION: Age-related macular degeneration has emerged as a paradigmatic example of a common disease caused by the interplay of genetic predisposition and exposure to modifiable risk factors.
Development of Choroidal Neovascularization in Rats With Advanced Intense Cyclic Light–Induced Retinal Degeneration
AbstractOBJECTIVES: To study the progressive changes of intense cyclic light-induced retinal degeneration and to determine whether it results in choroidal neovascularization (CNV). METHODS: Albino rats were exposed to 12 hours of 3000-lux cyclic light for 1, 3, or 6 months. Fundus examination, fundus photography, fluorescein and indocyanine green angiography, and optical coherence tomography were performed prior to euthanization. Light-exposed animals were euthanized after 1, 3, or 6 months for histopathological evaluation. Retinas were examined for the presence of 4-hydroxy-2-nonenal- and nitrotyrosine-modified proteins by immunofluorescence staining. RESULTS: Long-term intense cyclic light exposure resulted in retinal degeneration with loss of the outer segments of photoreceptors and approximately two-thirds of the outer nuclear layer as well as development of subretinal pigment epithelium neovascularization after 1 month. Almost the entire outer nuclear layer was absent with the presence of CNV, which penetrated the Bruch membrane and extended into the outer retina after 3 months. Absence of the outer nuclear layer, multiple foci of CNV, retinal pigment epithelial fibrous metaplasia, and connective tissue bands containing blood vessels extending into the retina were observed after 6 months. All intense light-exposed animals showed an increased presence of 4-hydroxy-2-nonenal and nitrotyrosine staining. Optical coherence tomographic and angiographic studies confirmed retinal thinning and leakiness of the newly formed blood vessels. CONCLUSIONS: Our results suggest that albino rats develop progressive stages of retinal degeneration and CNV after long-term intense cyclic light exposure, allowing the detailed study of the pathogenesis and treatment of age-related macular degeneration. CLINICAL RELEVANCE: The ability to study the progressive pathogenesis of age-related macular degeneration and CNV will provide detailed knowledge about the disease and aid in the development of target-specific therapy.
International Journal of Ophthalmology · 2021 · 30 citations · open access
Progress of clinical therapies for dry age-related macular degeneration
AbstractDry age-related macular degeneration (AMD) is a progressive blinding disease that currently affects millions of people worldwide with no successful treatment available. Significant research efforts are currently underway to develop therapies aimed at slowing the progression of this disease or, more notably, reversing it. Here the therapies which have reached clinical trial for treatment of dry AMD were reviewed. A thorough search of PubMed, Embase, and Clinicaltrials.gov has led to a comprehensive collection of the most recent strategies being evaluated. This review also endeavors to assess the status and future directions of therapeutics for this debilitating condition.
Lamivudine Inhibits<i>Alu</i>RNA-induced Retinal Pigment Epithelium Degeneration via Anti-inflammatory and Anti-senescence Activities
AbstractPurpose: Accumulation of the long noncoding Alu element RNA activates the NLRP3 inflammasome and leads to retinal pigment epithelium (RPE) cell death, a key event in the pathogenesis of geographic atrophy during late-stage age-related macular degeneration. Lamivudine (3TC) is a nucleoside analog reverse transcriptase inhibitor known to inhibit the NLRP3 inflammasome. Currently, the intracellular response of the senescence marker p16Ink4a to the long noncoding RNA is being actively studied. The present study aimed to assess the efficacy of 3TC against Alu RNA-induced RPE inflammation and senescence by evaluating changes in expression of the proinflammatory cytokines IL-18 and IL-1β and of p16INK4a in RPE cells. Methods: Cultured human RPE cells and in vivo mouse RPE cells were transfected with an in vitro-transcribed Alu RNA, and changes in IL-18, IL-1β, and p16Ink4a expression measured in the presences of 3TC or 3,4-(M)CA as a negative control. Results: Treatment with 3TC markedly reduced Alu RNA-induced expression of IL-18 and IL-1β in human and mouse RPE cells compared with the negative control. Further, Alu RNA-induced p16INK4a expression was suppressed by 3TC in human RPE cells. Conclusions: Our data suggest that Alu RNA accumulation contributes to RPE cell senescence in age-related macular degeneration and that this pathogenic process can be suppressed by 3TC. Translational Relevance: Further verifying this study leads to potential targets for age-related macular degeneration therapy.
Current Opinion in Ophthalmology · 2007 · 9 citations
Treatment of neovascular age-related macular degeneration: past, present and future directions
AbstractPURPOSE OF REVIEW: The treatment options of choroidal neovascularization due to age-related macular degeneration have expanded. Prior to ocular photodynamic therapy the only available treatment was laser photocoagulation. Clinicians and patients were not particularly enthusiastic despite its ability to stabilize vision. The purpose of the review is to review the past and current concepts of neovascular age-related macular degeneration therapy and to provide a short overview of upcoming treatments. RECENT FINDINGS: Photodynamic therapy provided us with the first realistic means to address subfoveal choroidal neovascularization lesions from age-related macular degeneration. Antivascular endothelial growth factors now allow better visual outcomes than mere stabilization of vision and other promising treatments are undergoing study at this time. SUMMARY: Age-related macular degeneration therapy has undergone a significant revolution in recent years. Understanding the historical perspective of treatment provides a better appreciation of current therapies. Still there is no cure for this disease and more promising treatments are currently under investigation.
Taiwan Journal of Ophthalmology · 2011 · 6 citations · open access
Pharmacological treatment of dry age-related macular degeneration (AMD)
AbstractAs the population grows older each year, age-related macular degeneration (AMD) is becoming the leading eye disease resulting in blindness. Although some drugs are available for the treatment of wet AMD, no drug is currently available for dry AMD. Actual research is taking place to invent novel drug for the treatment of dry AMD and the hurdles of the R&D are reviewed. Literature search and review were conducted to identify various ideas to treat dry AMD and to overcome the difficulties of developing clinical end points for developing the new drugs. Some promising drug candidates had been identified and clinical end points of drug efficacy determination had been collected. With the proof of new concepts and clinical end points available, the hope is high to expect some new novel drugs be put in the market sometime in the future.
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.
