DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Unverricht-Lundborg syndrome — 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 moduleUnverricht-Lundborg syndrome 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 unverricht-lundborg syndrome 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
scavenger receptor class B member 2 (SCARB2) — SCARB2 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 m6ddrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4Q4F · 2.8 Å · ligand 6-O-phosphono-beta-D-mannopyranose (M6D). Experimental structure, not a prediction.
What the evidence adds up to
Two randomised, double-blind, placebo-controlled phase III trials of adjunctive brivaracetam in patients with genetically confirmed Unverricht-Lundborg disease (EPM1) found no statistically significant effect on the primary endpoint, which was percent reduction from baseline in action myoclonus score. In study N01187 (50 patients randomised, 47 completed), the median reduction was 5.6% on placebo, 26.3% on 50 mg/day brivaracetam, and 16.9% on 150 mg/day brivaracetam. In study N01236 (56 patients randomised, 54 completed), the median reduction was 17.5% on placebo, -4.6% on 5 mg/day, and 12.3% on 150 mg/day. The estimated differences versus placebo were not statistically significant in either study. The authors noted wide intrapatient variability in the action myoclonus score and questioned whether it was the optimal tool for measuring myoclonus severity in EPM1. Treatment-emergent adverse events were reported by 72–75% of placebo-treated patients and 56–83% of brivaracetam-treated patients. Completion rates were very high (95.3% overall), and 88.7% of patients entered long-term follow-up, which the authors attributed to good tolerability.
A 2018 study investigated an antisense oligonucleotide strategy to correct the splicing mutation c.66G>A in the cystatin B (CSTB) gene in patient cells. A locked nucleic acid antisense oligonucleotide designed to block a cryptic splice site in intron 1 restored the normal splicing pattern in a sequence- and dose-specific manner. The authors described this as a proof of principle for a mutation-specific antisense therapy in Unverricht-Lundborg disease, but no clinical data in patients were reported.
A 2022 study used patient-derived induced pluripotent stem cells (iPSCs) and their neuronal derivatives from two Italian siblings with Unverricht-Lundborg disease who had different clinical severities. Both siblings were homozygous for the same dodecamer repeat expansion in the CSTB promoter, and luciferase assays showed similarly reduced CSTB promoter activity in both lines compared to controls. The authors concluded that the phenotypic differences between the siblings did not appear to depend strictly on the CSTB genetic mutation. In iPSC-derived neurons, they found increased expression of lysosomal cathepsins B, D, and L alongside reduced CSTB protein, but the increase in cathepsin expression did not correlate with the residual amount of CSTB, suggesting other mechanisms may be involved.
What remains missing is a validated, sensitive clinical endpoint for myoclonus in EPM1 that can detect a treatment effect in a trial setting. The antisense approach has not been tested in patients, and the cell-based work highlights that the molecular mechanisms driving disease severity are not yet fully understood, which complicates patient stratification for any future therapy.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Epilepsia · 2015 · 53 citations · open access
Brivaracetam in Unverricht‐Lundborg disease (<scp>EPM</scp>1): Results from two randomized, double‐blind, placebo‐controlled studies
AbstractOBJECTIVE: To evaluate efficacy, tolerability, and safety of adjunctive brivaracetam (BRV) in patients with Unverricht-Lundborg disease (EPM1). METHODS: Two prospective, multicenter, double-blind, phase III trials (N01187/NCT00357669; N01236/NCT00368251) in patients (≥16 years) with genetically ascertained EPM1, showing moderate-severe myoclonus (action myoclonus score ≥30/160), randomized (1:1:1) to twice-daily BRV (N01187: 50 or 150 mg/day; N01236: 5 or 150 mg/day), or placebo. Both studies comprised a baseline period (2 weeks), 2-week up-titration period, 12-week stable-dose maintenance period, and down-titration or entry into long-term follow-up study. Symptoms of myoclonus were assessed by Unified Myoclonus Rating Scale (UMRS). Primary efficacy end point was percent reduction from baseline in action myoclonus score (UMRS section 4) at last treatment visit. Safety assessments included treatment-emergent adverse events (TEAEs). RESULTS: N01187: 50 patients randomized, 47 completed; N01236: 56 patients randomized, 54 completed. Median (min-max) percent reduction from baseline in action myoclonus score is the following-N01187: placebo 5.6 (-81.3 to 53.8), pooled BRV group (primary efficacy analysis) 21.4 (-50.0 to 73.6), BRV 50 mg/day 26.3 (-35.8 to 69.2), BRV 150 mg/day 16.9 (-50.0 to 73.6); N01236: placebo 17.5 (-170 to 61.5), BRV 5 mg/day -4.6 (-430 to 81.8), BRV 150 mg/day (primary efficacy analysis) 12.3 (-58.3 to 96.9). Estimated differences versus placebo were not statistically significant. TEAEs were reported by 72-75% placebo-treated and 56-83% BRV-treated patients. SIGNIFICANCE: Effect of BRV on action myoclonus was not statistically significant. However, action myoclonus score showed wide intrapatient variability and may not have been the optimal tool to measure severity of myoclonus in EPM1. Both studies had very high completion rates (95.3% overall), and a high percentage of patients (88.7% overall) entered long-term follow-up; both likely to be influenced by good tolerability. These studies demonstrate the feasibility of rigorous trials in progressive myoclonic epilepsy.
Correction of a Splicing Mutation Affecting an Unverricht-Lundborg Disease Patient by Antisense Therapy
AbstractUnverricht-Lundborg disease (ULD) is a common form of progressive myoclonic epilepsy caused by mutations in the cystatin B gene (CSTB) that encodes an inhibitor of several lysosomal cathepsins. Presently, only pharmacological treatment and psychosocial support are available for ULD patients. To overcome the pathogenic effect of the ULD splicing mutation c.66G>A (exon 1), we investigated whether an antisense oligonucleotide therapeutic strategy could correct the defect in patient cells. A specific locked nucleic acid (LNA) antisense oligonucleotide was designed to block a cryptic 5′ss in intron 1. Overall, this approach allowed the restoration of the normal splicing pattern. Furthermore, the recovery was both sequence and dose-specific. In general, this work provides a proof of principle on the correction of a CSTB gene defect causing ULD through a mutation-specific antisense therapy. It adds evidence to the feasibility of this approach, joining the many studies that are paving the way for translating antisense technology into the clinical practice. The insights detailed herein make mutation-based therapy a clear candidate for personalized treatment of ULD patients, encouraging similar investigations into other genetic diseases.
Insights into the Genetic Profile of Two Siblings Affected by Unverricht-Lundborg Disease Using Patient-Derived hiPSCs
AbstractUnverricht-Lundborg disease (ULD), also known as progressive myoclonic epilepsy 1 (EPM1), is a rare autosomal recessive neurodegenerative disorder characterized by a complex symptomatology that includes action- and stimulus-sensitive myoclonus and tonic-clonic seizures. The main cause of the onset and development of ULD is a repeat expansion of a dodecamer sequence localized in the promoter region of the gene encoding cystatin B (CSTB), an inhibitor of lysosomal proteases. Although this is the predominant mutation found in most patients, the physio-pathological mechanisms underlying the disease complexity remain largely unknown. In this work, we used patient-specific iPSCs and their neuronal derivatives to gain insight into the molecular and genetic machinery responsible for the disease in two Italian siblings affected by different phenotypes of ULD. Specifically, fragment length analysis on amplified CSTB promoters found homozygous status for dodecamer expansion in both patients and showed that the number of dodecamer repeats is the same in both. Furthermore, the luciferase reporter assay showed that the CSTB promoter activity was similarly reduced in both lines compared to the control. This information allowed us to draw important conclusions: (1) the phenotypic differences of the patients do not seem to be strictly dependent on the genetic mutation around the CSTB gene, and (2) that some other molecular mechanisms, not yet clearly identified, might be taken into account. In line with the inhibitory role of cystatin B on cathepsins, molecular investigations performed on iPSCs-derived neurons showed an increased expression of lysosomal cathepsins (B, D, and L) and a reduced expression of CSTB protein. Intriguingly, the increase in cathepsin expression does not appear to be correlated with the residual amount of CSTB, suggesting that other mechanisms, in addition to the regulation of cathepsins, could be involved in the pathological complexity of the disease.
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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