DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for ocular hypotension — screening already-approved drugs against its 32-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleOcular hypotension maps to a 32-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 ocular hypotension 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
parvin alpha (PARVA) — PARVA 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 4rdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2VZC · 1.05 Å · ligand (4R)-2-METHYLPENTANE-2,4-DIOL (MRD). Experimental structure, not a prediction.
What the evidence adds up to
Topical ocular hypotensive medication delayed or prevented the onset of primary open-angle glaucoma in African American participants of the Ocular Hypertension Treatment Study. Among 408 African American participants randomised, 17 of 203 (8.4%) in the medication group developed POAG over a median follow-up of 78 months, compared with 33 of 205 (16.1%) in the observation group, a hazard ratio of 0.50 (95% CI 0.28–0.90, P = .02). This is the only randomised controlled evidence presented here, and it concerns a specific population with ocular hypertension, not ocular hypotension.
The soluble guanylate cyclase stimulator IWP-953 increased conventional outflow facility in enucleated mouse eyes ex vivo. At 100 μM, outflow facility increased by 89.5% (P = 0.002), comparable to the 97.5% increase seen with DETA-NO at the same concentration. In vitro, IWP-953 stimulated cGMP production in HEK-293 cells and in human trabecular meshwork cells, with a markedly greater effect in myofibroblast-like strains than in endothelial-like strains. A 2019 abstract reports that the hydrogen sulfide donor GYY 4137 lowered intraocular pressure in CBS-deficient mice fed a high methionine diet, and improved vision-related behaviour, but this is presented as a conference abstract with no quantitative IOP data or sample sizes.
Observational data on persistence with prostaglandin analogues show that uninterrupted use of the initial drug for a year is rare. In a claims analysis of 6271 patients, only 10% had uninterrupted use of the initial PGA alone or in combination for a year; 56% stopped and restarted, 16% switched, and 19% discontinued. Latanoprost had the highest persistence (11%) compared with bimatoprost (9%) and travoprost (5%, P < 0.0001). A separate clinical study of 145 patients with blunt ocular trauma found hypotony in 6.9%, with significantly higher rates in eyes with ciliochoroidal detachment (66.7%), traumatic retinal detachment (18.5%), and anterior proliferative vitreoretinopathy (42.9%).
The evidence base for treating ocular hypotension itself is thin. The randomised data address ocular hypertension, not hypotension. The preclinical work on IWP-953 and GYY 4137 is limited to mouse eyes and cell culture, with no human data, no safety assessment, and no information on dosing or formulation. The persistence data indicate that even established ocular hypotensive drugs are poorly adhered to, which would complicate any trial of a new agent. What is missing is any clinical trial of a drug specifically for ocular hypotension, any human data on sGC stimulators or H2S donors for this indication, and any patient stratification that distinguishes traumatic from non-traumatic causes.
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 · 2004 · 152 citations
The Ocular Hypertension Treatment Study
AbstractBACKGROUND: The prevalence of glaucoma is higher in African American individuals than in white individuals. OBJECTIVE: To report the safety and efficacy of topical ocular hypotensive medication in delaying or preventing the onset of primary open-angle glaucoma (POAG) among African American participants in the Ocular Hypertension Treatment Study. METHODS: Eligibility criteria included age between 40 and 80 years, intraocular pressure between 24 and 32 mm Hg in one eye and between 21 and 32 mm Hg in the other eye, and no evidence of glaucomatous structural or functional damage by standard clinical measures. Participants were randomized to either the observation group or medication group. Of the 1636 participants randomized, 408 were self-identified as African American. MAIN OUTCOME MEASURE: The primary outcome was the development of reproducible visual field abnormality and/or reproducible optic disc deterioration attributed to POAG. RESULTS: Among African American participants, 17 (8.4%) of 203 in the medication group developed POAG during the study (median follow-up, 78 months) compared with 33 (16.1%) of 205 participants in the observation group (hazard ratio, 0.50; 95% confidence interval, 0.28-0.90; P =.02). CONCLUSION: Topical ocular hypotensive therapy is effective in delaying or preventing the onset of POAG in African American individuals who have ocular hypertension.
Therapeutics and Clinical Risk Management · 2006 · 62 citations · open access
The management of glaucoma and intraocular hypertension: current approaches and recent advances
AbstractIn the last decade, numerous novel ocular hypotensive agents have been introduced for the control of intraocular pressure (IOP). Clinicians now have more options than ever in the selection of medical therapy for the treatment of glaucoma and ocular hypertension. When selecting an ocular hypotensive medication for their patients, clinicians should consider not only the IOP-lowering efficacy of an agent, but also the ability of the drug to allow patients to achieve target levels of IOP that are low enough to stop the progression of glaucomatous damage. Other considerations should include how well the drug controls diurnal IOP, the likelihood of serious adverse events, the versatility of the medication for use as an adjunctive agent, as well as other potential attributes (ie, neuroprotection).
The Soluble Guanylate Cyclase Stimulator IWP-953 Increases Conventional Outflow Facility in Mouse Eyes
AbstractPURPOSE: The nitric oxide (NO)-cyclic guanosine-3',5'-monophosphate (cGMP) pathway regulates aqueous humor outflow and therefore, intraocular pressure. We investigated the pharmacologic effects of the soluble guanylate cyclase (sGC) stimulator IWP-953 on primary human trabecular meshwork (HTM) cells and conventional outflow facility in mouse eyes. METHODS: Cyclic GMP levels were determined in vitro in HEK-293 cells and four HTM cell strains (HTM120/HTM123: predominantly myofibroblast-like phenotype, HTM130/HTM141: predominantly endothelial-like phenotype), and in HTM cell culture supernatants. Conventional outflow facility was measured following intracameral injection of IWP-953 or DETA-NO using a computerized pressure-controlled perfusion system in enucleated mouse eyes ex vivo. RESULTS: IWP-953 markedly stimulated cGMP production in HEK-293 cells in the presence and absence of DETA-NO (half maximal effective concentrations: 17 nM, 9.5 μM). Similarly, IWP-953 stimulated cGMP production in myofibroblast-like HTM120 and HTM123 cells, an effect that was greatly amplified by the presence of DETA-NO. In contrast, IWP-953 stimulation of cGMP production in endothelial-like HTM130 and HTM141 cells was observed, but was markedly less prominent than in HTM120 and HTM123 cells. Notably, cGMP was found in all HTM culture supernatants, following IWP-953/DETA-NO stimulation. In paired enucleated mouse eyes, IWP-953 at 10, 30, 60, and 100 μM concentration-dependently increased outflow facility. This effect (89.5%) was maximal at 100 μM (P = 0.002) and in magnitude comparable to DETA-NO at 100 μM (97.5% increase, P = 0.030). CONCLUSIONS: These data indicate that IWP-953, via modulation of the sGC-cGMP pathway, increases aqueous outflow facility in mouse eyes, suggesting therapeutic potential for sGC stimulators as novel ocular hypotensive drugs.
Clinical study on Hypotony following blunt ocular trauma.
AbstractAIM: To evaluate the incidence and risk factors of hypotony in patients with blunt ocular trauma. METHODS: The medical records of 145 patients with blunt ocular trauma were reviewed. Hypotony was defined as an average intraocular pressure (IOP) of 5mmHg or less for three times. RESULTS: Among these 145 patients, hypotony was noted in 10 (6.9%) patients. The rate of hypotony in patients with ciliochoroidal detachment was 66.7% (2 out of 3 eyes), and 5.6% (8 out of 142 eyes) in patients without ciliochoroidal detachment, the difference was statistically significant (P=0.003). The rate of hypotony in patients with traumatic retinal detachment was 18.5% (5 out of 27 eyes), and 4.2% (5 out of 118 eyes) in patients without traumatic retinal detachment, the difference was statistically significant (P=0.026). The rate of hypotony in the patients with anterior proliferative vitreoretinopathy was 42.9% (3 out of 7 eyes) and 5.1% (7 out of 138 eyes) in the patients without anterior proliferative vitreoretinopathy, the difference was statistically significant (P=0.002). CONCLUSION: Ocular hypotension is a complication of blunt ocular trauma. The risk factors include ciliochoroidal detachment, traumatic retinal detachment, and anterior proliferative vitreoretinopathy.
Current Medical Research and Opinion · 2010 · 16 citations
Physicians’ treatment decisions, patient persistence, and interruptions in the continuous use of prostaglandin therapy in glaucoma
AbstractBACKGROUND: Uninterrupted use of ocular hypotensive medication by glaucoma patients is important to prevent vision loss, but medication persistence is poor. Efficacy and tolerability influence physicians' decisions and patient persistence, and differences between medications may impact persistence. OBJECTIVE: To examine differences in physician's decisions to continue, switch, or discontinue therapy across three prostaglandin analogs (PGAs) latanoprost, bimatoprost, and travoprost using claims data supplemented by evaluation of physicians' charted therapeutic decisions. METHODS: A year of pharmacy claims data for 6271 patients with a first (index) fill between 5/1/2001 and 11/30/2004 for PGA monotherapy were classified as 'persistent', 'switched', 'restarted', or 'discontinued' with initial PGA use. An analysis of index therapy continuation during the first 2 years reflected chart reviews for 223 patients with PGA monotherapy as the index prescription. RESULTS: Ten percent of patients had uninterrupted use of the initial PGA alone or in combination for a year. More than half (56%) stopped and then restarted, 16% switched, and 19% discontinued the initial PGA. Patients using latanoprost were more likely to be persistent (11%) compared to bimatoprost (9%) or travoprost (5%; p < 0.0001 overall comparison). Overall, 68% of patients on latanoprost persisted or restarted after a gap compared to 61% for bimatoprost and 58% for travoprost (p < 0.0001). Patient charts demonstrated a parallel pattern in physicians' decisions to continue latanoprost (56%), bimatoprost (45%), and travoprost (40%). Study limitations included the inability to establish causal links between variables, to account for sample use, or to document reasons for patient-driven changes in therapy. The study should be replicated in a more recent database including a larger population. CONCLUSIONS: Uninterrupted use of ocular hypotensive therapy for a full year is relatively rare. Differences in physicians' decisions to continue, switch, or discontinue PGAs were observed in claims data, and parallel trends were observed in patient medical records.
Abstract P159: Reversing Ocular Hypertension and Blindness by Hydrogen Sulfide
AbstractHyperhomocysteinemia (HHcy) is associated with glaucoma, sphincter-muscle atrophy and retinal artery/vein occlusion, mechanisms are unclear. Results show HHcy as a hallmark of epigenetic dysfunction that leads to decrease in H 2 S, a potent vasoactive transmitter, anti-inflammatory and anti-oxidant. HHcy antagonizes beta-2 adrenergic receptor and decreases Gαs subunit. In addition, HHcy causes reduction in H 2 S by decrease in cystathionine β synthase (CBS) and cystathionine γ lyase (CSE). However, it is unclear whether decrease in H 2 S increases ocular pressure and causes blindness. Central hypothesis of this project is that epigenetic-hypermethylation by DNMTs causes decrease in H 2 S, CBS, CSE and MTHFR that lead to retinal vascular dysfunction causing blindness. Increase in H 2 S mitigates blindness (Fig. 1). CBS +/- and WT mice fed with/without high methionine diet were administered either PBS or H 2 S donor; GYY 4137. Lysates for key-proteins, glutamate and glutathione were examined. Intraocular pressure (IOP) was monitored; barium sulfate and BSA-FITC angiographies were performed for vasculature/permeability. Vision was tested employing novel object recognition test (NORT) and light-dark box test (LDBT). CBS deficiency with HMD led disruption of metabolism leading to HHcy as reflected by increased Hcy and S-adenosylhomocysteine hydrolase. Unlike CBS, CSE and MTHFR were reduced but compensated by GYY 4137. Oxidative/ER stress was mitigated by GYY 4137 with enhanced GSH. Increased glutamate in CBS +/- was prominent than WT and these mice exhibited higher IOP that was lowered by GYY 4137. CBS-deficiency resulted in vision impairment as revealed by NORT/LDBT. GYY 4137 improved CBS +/- behavior together with lowering their glutamate. BRB appeared compromised in CBS +/- with vessel leakage that was mitigated by GYY 4137 corroborating results for occludin stabilization. Findings reveal that HHcy-induced glutamate excitotoxicity, oxidative damage, ER-stress and permeability can compromise vision and GYY 4137 could serve as a therapeutic agent for ocular hypertension and blindness.
AbstractChanging initial ocular hypotensive therapy is common. Individuals who undergo a change in therapy required more frequent face-to-face monitoring and incurred higher healthcare related costs. Identifying strategies capable of optimizing the process of initiating ocular hypotensive therapy are appealing and possess the potential to improve patient outcomes and reduce healthcare costs.
Journal of Neuro-Ophthalmology · 2009 · 0 citations
Garner and Klintworth's Pathobiology of Ocular Diseases, 3rd Edition
AbstractGordon K. Klintworth, PhD, and Alec Garner, MD, PhD. Informa Healthcare, New York, 2008. ISBN 978-0-8493-9816-2, $699.95. Scope: This two-volume set encompasses current knowledge of anatomic pathology, cell biology, molecular biology, and biochemistry of ocular disease. Numerous authors provide a multidisciplinary depth of information unmatched in current eye pathology texts. The book is organized by mechanisms rather than anatomic areas. Unification of the chapter format is achieved from a set outline permitting easy transition between chapters despite the multiple writers. A great deal of space has been allocated for detailed presentations of etiologic aspects of various disease processes. The intended audience includes ocular pathologists, neuropathologists, ophthalmologists, and scientists working in disciplines such as immunology, genetics, and cell biology. Strengths: This unique textbook is designed to promote the understanding of disease processes. It is meticulously referenced and contains an enormous amount of detail concerning the genetics and cell biology of ocular disease. Most chapters provide interesting historical information, superb pathophysiologic explanations, and exhaustive tables. The outstanding quality of many chapters such as Genetic Disorders of the Cornea, authored by Klintworth, exemplifies the expertise of the authors. Weaknesses: Illustrations, all black and white, vary in quality. The ambitious attempt to explore the pathogenesis of so many topics has taken some authors to their limits and accounts for some omissions. For example, tear lipocalin, a siderophore binding protein, is overlooked in the discussion of microbial competition for iron in the tear film. To stay current, the work will require frequent updates. Recommended Audience: This is an excellent reference textbook for scientists and pathologists who work with the eye. The book's comprehensive nature may be overwhelming as a primer for residents training in ophthalmology, but the book will be a superb reference source for them. Critical Appraisal: This book is an outstanding contribution to the field of ophthalmic pathology. It provides a comprehensive overview not found in any other work in our discipline. Ben Glasgow, MD Department of Pathology and Laboratory Medicine University of California, Los Angeles Los Angeles, California
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.
