DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for microcephaly and chorioretinopathy 3 — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleMicrocephaly and chorioretinopathy 3 maps to a 2-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 microcephaly and chorioretinopathy 3 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
tumor protein p53 binding protein 1 (TP53BP1) — TP53BP1 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5ECG · 3.0 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Microcephaly and chorioretinopathy 3 is not named in any of the provided abstracts. The abstracts cover two separate conditions: Seckel Syndrome and Primary Microcephaly (MCPH), and central serous chorioretinopathy (CSC). No abstract links a single drug or mechanism to both microcephaly and chorioretinopathy in the same disorder.
In the microcephaly literature, Seckel Syndrome and Primary Microcephaly are defined by head circumference less than three standard deviations below the mean. ATR-Seckel Syndrome is caused by mutations in the ATR kinase, which activates a DNA damage signalling response. Cell lines from other Seckel patients who are normal for ATR show defective ATR signalling, suggesting mutations in other components of the ATR pathway. MCPH1, the first identified Primary Microcephaly gene, encodes three BRCT domains similar to damage response proteins. MCPH1 functions in the ATR-dependent DNA damage response pathway and also has an ATR-independent role in regulating mitotic entry, producing premature chromosome condensation. No drug treatment is described for either condition in these abstracts.
For central serous chorioretinopathy, several drug interventions are reported. In a retrospective cohort of 93 patients, mineralocorticoid-receptor antagonists and acetazolamide both significantly improved highest retinal prominence and subretinal fluid volume at 12 weeks (mineralocorticoid-receptor antagonist: p = 0.0000003 for prominence, p = 0.008 for volume; acetazolamide: p < 0.0000001 for prominence, p = 0.0000007 for volume). Visual acuity improved significantly in both treated groups (acetazolamide p = 0.002, mineralocorticoid-receptor antagonist p = 0.03). Observation alone showed improvement without statistical significance. In acetazolamide non-responders, switching to a mineralocorticoid-receptor antagonist improved outcomes, but switching in the opposite direction did not. A separate challenge-rechallenge case report describes spironolactone as effective for CSC secondary to steroid use. A retrospective study of 43 patients found that discontinuing or replacing drugs that are substrates or inhibitors of cytochrome P450 3A4 (including steroids, calcium channel blockers, statins, and others) led to improvement in 18 of 27 patients (22 eyes); none of the patients using such drugs improved with eplerenone therapy. In 21 of 22 eyes, subretinal fluid absorption was observed, and mean central retinal thickness decreased from 361 μm to 219 μm.
A one-year prospective study of 38 untreated acute CSC patients found that choroidal thickness decreased by a mean of 58.1 µm (95% CI 30.1–85.9) from baseline, and subretinal fluid resolved in 67% (95% CI 51–82) of patients at 6 months. Best-corrected visual acuity improved over time (decrease of logMAR 0.086, 95% CI 0–0.172). No prognostic factors (baseline choroidal thickness, macular thickness, visual acuity, age, or sex) predicted the need for treatment. A review of literature on CSC states that there is no common point of view and that approaches to treatment of acute and chronic forms are contradictory.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Cell Cycle · 2006 · 45 citations · open access
Microcephalin: A Causal Link Between Impaired Damage Response Signalling and Microcephaly
AbstractSeckel Syndrome (SS) and Primary Microcephaly (MCPH) are disorders exhibiting marked microcephaly with a head circumference less than three standard deviations below the mean. ATR-Seckel Syndrome is conferred by mutations in ataxia and telangiectasia and Rad3 related (ATR), a kinase that activates a DNA damage signalling response. Cell lines from additional SS patients, who are normal for ATR, show defective ATR signalling, suggesting that they carry mutations in other components of the ATR pathway. Primary Microcephaly is distinct from SS since patients display solely microcephaly without accompanying marked growth delay. MCPH1, the first Primary Microcephaly causative gene identified, encodes three BRCT domains, similar to other damage response proteins. Recent studies employing MCPH1 siRNA or exploiting cell lines from MCPH1 patients have shown that MCPH1 functions in the ATR-dependent DNA damage response pathway. Additionally, MCPH1 has a function in the regulation of mitotic entry that is ATR-independent and confers a characteristic phenotype of premature chromosome condensation. Recent studies will be reviewed and their relationship to the aetiology of microcephaly discussed.
Journal of Ocular Pharmacology and Therapeutics · 2017 · 12 citations
Therapy Rationale for Mineralocorticoid-Receptor Antagonists, Acetazolamide and a Switch of Therapy in Nonresponders in Central Serous Chorioretinopathy
AbstractPURPOSE: To evaluate the efficacy of mineralocorticoid-receptor antagonists in comparison to acetazolamide and observation in the treatment of central serous chorioretinopathy. METHODS: Retrospective, interventional cohort study on 93 patients with acute or chronic central serous chorioretinopathy (37 patients: acetazolamide group, 20 patients: mineralocorticoid-receptor antagonist group, 8 patients: observation group, and 27 patients with a therapy switch between both medications). Main outcome measures were the change in best-corrected visual acuity, subretinal fluid (SRF) volume, central retinal prominence, and highest retinal prominence (HRP) at 12 weeks. RESULTS: HRP and SRF volume improved with statistical significance (P ≤ 0.05) after mineralocorticoid-receptor antagonist (P = 0.0000003 for the prominence, P = 0.008 for the volume) and acetazolamide (P < 0.0000001 for the prominence, P = 0.0000007 for the volume) treatment. HRP and SRF volume also improved after observation, but without statistical significance (P = 0.08 for the prominence, P = 0.72 for the volume). Corresponding visual acuity improved significantly in acetazolamide (P = 0.002) and mineralocorticoid-receptor antagonist (P = 0.03) treated patients. Interestingly, HRP and SRF volume in acetazolamide nonresponsive patients improved after switch to mineralocorticoid-receptor antagonists, whereas no benefit was seen in patients switching vice versa. CONCLUSIONS: Both medical treatments are effective first-line treatment options for central serous chorioretinopathy. In patients who are nonresponsive to acetazolamide, therapy switch to mineralocorticoid-receptor antagonists could be beneficial.
AbstractThis is a report of seven new cases of microcephaly with chorioretinopathy. Three cases were sporadic and four were dominant: a father and son, and a father and daughter. Their ophthalmological, neurological, and systemic findings are discussed as are the genetics of the syndrome. Chorioretinopathy with characteristic punched-out lesions was observed in both entities. Body height emerges as a possible distinguishing feature between the dominant and recessive forms. In addition, locomotor disturbances are more frequently seen in patients with the recessive form.
Clinical and Experimental Optometry · 2022 · 6 citations
One-year follow-up of choroidal and macular thickness in acute non-treated central serous chorioretinopathy
AbstractClinical relevance Choroidal and macular thickness assessments are essential to understand the evolution of central serous chorioretinopathy and could help in identifying patients more prone to recurrence.Background The aim of this work was to evaluate changes in the choroidal thickness and macular thickness in acute non-treated central serous chorioretinopathy during a one-year follow-up.Methods A prospective longitudinal study of 38 patients with central serous chorioretinopathy and 35 healthy controls at a tertiary care facility (Fundación Alcorcón University Hospital) was conducted. Choroidal and macular thicknesses were measured using enhanced-depth-imaging optical coherence tomography and subretinal fluid resolution and best-corrected visual acuity were evaluated, at baseline and 1, 3, 6 and 12 months. Prognostic factors determining the need for treatment were evaluated.Results Choroidal thickness decreased in eyes with central serous chorioretinopathy (p < 0.001) but not in fellow eyes (p = 0.24) during one-year follow-up since the acute episode. The estimated mean choroidal thickness in symptomatic eyes was 465 µm (SE: 17.18) at baseline and decreased 58.1 µm (CI 95%: 30.1-85.9) at 12 months (p < 0.001). Best-corrected visual acuity improved over time (p = 0.037), with a decrease of logMAR 0.086 (CI95%: 0-0.172).The macular thickness changed over time (p < 0.001), with a decrease from baseline of 124.6 µm (CI95%: 61.4-187.9). Subretinal fluid resolved in 67% (CI 95%: 51-82) of patients at 6 months. There was no significant association between baseline choroidal thickness, macular thickness, best-corrected visual acuity, age or sex and the need for treatment.Conclusions The choroidal thickness decreased in acute central serous chorioretinopathy episodes during a one-year follow-up. Subretinal fluid persisted in less than 20% of patients at the end of the one-year follow-up. No prognostic factors determining the need for treatment were found.
Chorioretinopathy and Microcephaly with Normal Development
AbstractPURPOSE: To report a pediatric patient with bilateral chorioretinopathy and microcephaly who from birth to 2 years of age is reaching appropriate developmental milestones. DESIGN: Retrospective case report with clinical findings and literature review. MAIN OUTCOME MEASURES: Clinical findings and visual acuity estimated by sweep visual evoked potentials (VEP), electroretinogram (ERG) and fundoscopic exam. RESULTS: A microcephalic child with normal motor and cognitive development had improving sweep VEP despite atypical fundoscopic findings of bilateral chorioretinopathy, attenuated retinal vessels, and anomalous optic nerves. The etiology for these collective findings despite extensive workup, including prenatal TORCH titers and neuro-imaging, has remained unidentified. CONCLUSIONS: Most published cases of microcephaly with chorioretinopathy have described patients with mild to severe mental retardation. Patients with chorioretinopathy and microcephaly may, however, reach all developmental milestones with improvement in visual development as was seen in this case. The long-term cognitive and visual prognosis may be better than previously reported.
Central serous chorioretinopathy induced by drugs metabolized by cytochrome P450 3A4.
AbstractThe purpose of this study was investigate whether replacing or discontinuing drugs that are inhibitors or substrates of cytochrome P450 3A4 (CYP3A4) may improve the clinical course of central serous chorioretinopathy (CSC). A retrospective observational study included 43 patients with active CSC. Twenty seven patients (32 eyes, group 1) were using drugs that act as substrates or inhibitors of CYP3A4. In 25 of these 27 patients, treatments including steroids, calcium channel blockers, anticoagulants, statins, beta-adrenolytics, angiotensin receptor antagonists, antidepressants, muscarinic receptor antagonists, phosphodiesterase type 5 inhibitors, and others were discontinued or replaced with medications not affecting CYP3A4. Sixteen patients (19 eyes, group 2) not using any medication that affects CYP3A4, were given eplerenone, rifampicin, or laser treatment. Main outcomes measures were assessed by functional and anatomical images obtained using multimodal imaging techniques. The average follow-up time was 12 months. In group I after discontinuing or replacing substrates or inhibitors of CYP3A4, improvements were observed in 18 patients (22 eyes). None of the patients that were using drugs affecting CYP3A4 improved with eplerenone therapy, however, all 18 patients improved after discontinuing the drugs. All these drugs had a blocking effect on eplerenone therapy. Best corrected visual acuity (BCVA) improved in 14 eyes, remained unchanged in 5 eyes, and worsened in 3 eyes. In 21 of the 22 eyes, subretinal fluid absorption was observed with optical coherence tomography (OCT). Mean central retinal thickness decreased from 361 μm to 219 μm. One patient (2 eyes) was unable to change treatment (due to neoplasm), one patient (1 eye) did not agree to change or stop treatment, and seven patients (7 eyes) were lost to follow-up. Of the 16 patients (19 eyes) who were treated with eplerenone, rifampicin, or laser, improvements were observed in 14 patients (16 eyes), two patients (2 eyes) were lost to follow-up, and CSC worsened in 1 eye. We concluded that patients with CSC should not take substrates or inhibitors of CYP3A4. These drugs should be replaced with alternatives that act through other metabolic pathways.
Case Reports in Ophthalmology · 2017 · 2 citations · open access
Spironolactone for Secondary Central Serous Chorioretinopathy: A Challenge-Rechallenge Case
AbstractCentral serous chorioretinopathy (CSCR) is potentially sight-threatening and has been associated with corticosteroid use. CSCR secondary to steroid use can sometimes be challenging to treat, especially if continuing steroid use is medically necessary. In this case report we demonstrate the efficacy of spironolactone as an effective agent in countering CSCR secondary to steroid use. This challenge-rechallenge case may be helpful to clinicians in delineating a treatment paradigm for these patients.
International Journal of Clinical Pediatrics · 2017 · 1 citations · open access
Microcephaly-Lymphedema-Chorioretinal Dysplasia Syndrome: Two Case Reports
AbstractMicrocephaly-lymphedema-chorioretinal dysplasia is a rare syndrome in which the component of chorioretinopathy may develop later. We describe two patients with microcephaly-lymphedema-chorioretinal dysplasia syndrome who had characteristic facial features and congenital heart defects. Second patient had also lissencephaly which was very rarely reported before. Int J Clin Pediatr. 2017;6(3-4):42-45 doi: https://doi.org/10.14740/ijcp275w
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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