DeCure for Developmental and epileptic encephalopathy 89
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for developmental and epileptic encephalopathy 89 — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleDevelopmental and epileptic encephalopathy 89 maps to a 1-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 developmental and epileptic encephalopathy 89 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
glutamate decarboxylase 1 (GAD1) — GAD1 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 hlddrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3VP6 · 2.1 Å · ligand 4-oxo-4H-pyran-2,6-dicarboxylic acid (HLD). Experimental structure, not a prediction.
What the evidence adds up to
A 2024 case report describes a 4-month-old girl with intractable epilepsy in whom most antiepileptic drugs were ineffective. High doses of phenytoin suppressed seizures, so a sodium channelopathy was suspected. Targeted DNA sequencing revealed a pathogenic missense variant Val1315Met in the SCN8A gene. After diagnosis, combination therapy with sodium channel blockers was initiated and seizures resolved. The authors note that even when a single sodium channel blocker is insufficient, combination therapy can lead to seizure freedom in SCN8A developmental and epileptic encephalopathy. This is a single case, not a trial.
A 2023 study from a reference centre in Northeast Brazil states that by August 2022 there were 105 genes associated with developmental and epileptic encephalopathy according to OMIM. The paper does not report any treatment outcomes or drug responses. A 2016 in silico prioritisation study used coexpression with 51 established epileptic encephalopathy genes to rank candidate genes genome-wide. Among 297 genes ranked in the top 10% for both adult and developing brain data sets, nine had been previously implicated in epileptic encephalopathies: FBXO41, PLXNA1, ACOT4, PAK6, GABBR2, YWHAG, NBEA, KNDC1, and SELRC1. The authors propose these as strong candidates for further investigation.
A 2018 review of de novo variants in epileptic encephalopathies notes that evaluating pathogenicity requires recurrence of variants in unrelated cases, information on previously defined phenotypes, and data from genetic experimental studies. The review states that genes related to epileptic encephalopathy reveal pathogenicity with distinct functional alterations — either gain of function or loss of function in the majority — but several genes warrant further study. A 2015 review on optimising seizure control and developmental outcome in epileptic encephalopathies advances concrete steps that may help improve developmental outcomes but does not report any specific drug results.
What is still missing: prospective trials of sodium channel blocker combinations in SCN8A-DEE beyond single case reports, systematic functional validation of the nine candidate genes proposed in 2016, and any randomised evidence that earlier genetic diagnosis changes developmental outcomes. Patient stratification by specific gene and variant type remains largely hypothetical.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Genetics in Medicine · 2018 · 61 citations · open access
Evaluating the pathogenic potential of genes with de novo variants in epileptic encephalopathies
AbstractEpileptic encephalopathies comprise a group of catastrophic epilepsies with heterogeneous genetic etiology. Although next-generation sequencing techniques can reveal a number of de novo variants in epileptic encephalopathies, evaluating the pathogenicity of these variants can be challenging. Determining the pathogenic potential of genes in epileptic encephalopathies is critical before evaluating the pathogenicity of variants identified in an individual. We reviewed de novo variants in epileptic encephalopathies, including their genotypes and functional consequences. We then evaluated the pathogenic potential of genes, with the following additional considerations: (1) recurrence of variants in unrelated cases, (2) information of previously defined phenotypes, and (3) data from genetic experimental studies. Genes related to epileptic encephalopathy revealed pathogenicity with distinct functional alterations, i.e., either a gain of function or loss of function in the majority; however, several genes warranted further study to confirm their pathogenic potential. Whether a gene was associated with distinct phenotype, the genotype (or functional alteration)--phenotype correlation, and quantitative correlation between genetic impairment and phenotype severity were suggested to be specific evidence in determining the pathogenic role of genes. Data from epileptic encephalopathy-related genes would be helpful in outlining guidelines for evaluating the pathogenic potential of genes in other genetic disorders.
Epileptic encephalopathies: Optimizing seizure control and developmental outcome
AbstractCognitive and developmental outcomes in patients with epileptic encephalopathy are hypothesized to result from an interplay between the underlying epileptic pathologic substrate and the acquired consequences of frequent and repetitive seizures and epileptiform discharges that often straddle the interictal and ictal boundaries. This article briefly reviews the evidence related to this assumption, presents critical questions that need to be answered to clarify this relationship, and advances a set of concrete steps that may help improve developmental patient outcomes.
Neurology Genetics · 2016 · 22 citations · open access
In silico prioritization based on coexpression can aid epileptic encephalopathy gene discovery
AbstractOBJECTIVE: To evaluate the performance of an in silico prioritization approach that was applied to 179 epileptic encephalopathy candidate genes in 2013 and to expand the application of this approach to the whole genome based on expression data from the Allen Human Brain Atlas. METHODS: PubMed searches determined which of the 179 epileptic encephalopathy candidate genes had been validated. For validated genes, it was noted whether they were 1 of the 19 of 179 candidates prioritized in 2013. The in silico prioritization approach was applied genome-wide; all genes were ranked according to their coexpression strength with a reference set (i.e., 51 established epileptic encephalopathy genes) in both adult and developing human brain expression data sets. Candidate genes ranked in the top 10% for both data sets were cross-referenced with genes previously implicated in the epileptic encephalopathies due to a de novo variant. RESULTS: Five of 6 validated epileptic encephalopathy candidate genes were among the 19 prioritized in 2013 (odds ratio = 54, 95% confidence interval [7,∞], p = 4.5 × 10(-5), Fisher exact test); one gene was false negative. A total of 297 genes ranked in the top 10% for both the adult and developing brain data sets based on coexpression with the reference set. Of these, 9 had been previously implicated in the epileptic encephalopathies (FBXO41, PLXNA1, ACOT4, PAK6, GABBR2, YWHAG, NBEA, KNDC1, and SELRC1). CONCLUSIONS: We conclude that brain gene coexpression data can be used to assist epileptic encephalopathy gene discovery and propose 9 genes as strong epileptic encephalopathy candidates worthy of further investigation.
Brain and Development Case Reports · 2024 · 2 citations · open access
A case of SCN8A-related developmental epileptic encephalopathy diagnosed by clinical speculation driven targeted DNA sequencing and remission of epilepsy by sodium channel blockers combination therapy
AbstractSCN8A-related epilepsy and/or neurodevelopmental disorders encompass a very broad spectrum of phenotypes. The most severe form, SCN8A developmental and epileptic encephalopathy (DEE), develops intractable epilepsy from early infancy and can lead to sudden death. Early diagnosis and therapeutic intervention are essential, but diagnosis is based on genetic testing and definitive diagnosis is often delayed. A 4-month-old girl presented with intractable epilepsy. Most antiepileptic drugs were ineffective, but high doses of phenytoin suppressed seizures, so a sodium channelopathy was suspected and targeted DNA sequencing was performed, which revealed a pathogenic missense variant Val1315Met in the SCN8A gene. Based on the diagnosis, combination therapy with sodium channel blockers (SCBs) was initiated and the seizures resolved. We experienced SCN8A-DEE, which led to early diagnosis based on clinical course and improved prognosis. It is noteworthy that even when the effect of a single SCB is insufficient, as in this case, combination therapy can lead to seizure free in SCN8A-DEE.
Journal of Pediatric Neurology · 2024 · 1 citations
SCN8A Encephalopathy with a Significant Long-Term Response to Lacosamide
AbstractAbstract Developmental and epileptic encephalopathy associated with SCN8A variants (i.e., SCN8A encephalopathy) causes early-onset epilepsy, involuntary movements, hypotonia, and developmental delay. Sodium channel blockers are effective for treating SCN8A encephalopathy; however, the long-term effects are unknown. Herein, we report the long-term efficacy of lacosamide (LCM) treatment in a patient with SCN8A encephalopathy. Our patient, a 7-year-old girl, presented with a hyperekplexia-like excessive startle response, drug-resistant epilepsy with sinus arrest, and prolonged respiratory failure during the neonatal period. The patient was diagnosed with SCN8A encephalopathy caused by a de novo pathogenic variant of SCN8A: c.3979A > G; p.Ile1327Val. The patient experienced tonic clustered seizures daily, with dramatic responses to high doses of LCM, lasting approximately 3 years.
Arquivos de Neuro-Psiquiatria · 2023 · 0 citations · open access
Genetic profile of patients with developmental and epileptic encephalopathy at a reference center in Northeast Brazil
AbstractBackground: The developmental and epileptic encephalopathy (DEE) diseases where there is developmental impairment related to both the underlying etiology independent of epileptiform activity and the epileptic encephalopathy. Many DEEs have a genetic basis that, by themselves, can alter the neurodevelopmental delay. By August 2022, there were 105 genes associated with DEE according to OMIM.
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.
