DeCure for Developmental and epileptic encephalopathy, 17
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for developmental and epileptic encephalopathy, 17 — 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, 17 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, 17 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
G protein subunit alpha o1 (GNAO1) — GNAO1 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 8alphadrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9BSB · 2.32 Å · ligand (8alpha)-N,N-diethyl-6-methyl-9,10-didehydroergoline-8-carboxamide (7LD). Experimental structure, not a prediction.
What the evidence adds up to
Two sisters born in 2004 and 2006 with early-onset epileptic encephalopathy began having infantile spasms at six months of age, later progressing to recurrent, treatment-resistant seizures. Whole-genome sequencing of the sisters and their unaffected parents revealed compound heterozygous mutations in the UBA5 gene: a paternally inherited exonic splicing mutation (c.684G > A) predicted to cause loss-of-function of one allele, and a maternally inherited missense mutation (p.Ala371Thr) previously reported as pathogenic when paired with a loss-of-function mutation. Three adult Icelanders homozygous for p.Ala371Thr showed no signs of neurological disease, supporting that this is a hypomorphic allele. The compound heterozygous genotype was absent from an Icelandic reference set of 30,067 individuals and from public databases. This was the first description of UBA5 mutations since the initial 2016 discovery that biallelic variants in the gene cause early-onset epileptic encephalopathy.
UBA5 encodes an activating enzyme for ufmylation, a post-translational modification mechanism, and is the first gene from the ufmylation pathway linked to disease. In a separate study, an in silico prioritization approach based on coexpression with 51 established epileptic encephalopathy genes in both adult and developing human brain data sets identified 297 genes ranked in the top 10% for both data sets. Of these, nine had been previously implicated in epileptic encephalopathies: FBXO41, PLXNA1, ACOT4, PAK6, GABBR2, YWHAG, NBEA, KNDC1, and SELRC1. The same approach had previously prioritized 19 of 179 candidate genes in 2013; five of six subsequently validated epileptic encephalopathy genes were among those 19 (odds ratio 54, 95% confidence interval 7 to infinity, p = 4.5 × 10⁻⁵), with one false negative.
Childhood epilepsy includes age-dependent syndromes categorised into a self-limited group with good prognosis and a pharmacoresistant group with poor prognosis. Many children develop pharmacoresistant epilepsy beginning in early infancy and progress to developmental epileptic encephalopathy, associated with intellectual, behavioural, or motor disabilities. These children do not show remission and require comprehensive medical care into adulthood. The relationship between the underlying epileptic pathologic substrate and acquired consequences of frequent seizures and epileptiform discharges remains poorly understood, and concrete steps to improve developmental outcomes have been proposed but not yet established.
What is still missing is a clear understanding of how UBA5 dysfunction leads to the specific seizure phenotype, and whether the ufmylation pathway offers any point for intervention. No clinical trial has tested any drug in patients with UBA5-related encephalopathy. The genetic diagnosis itself does not yet change management, and the natural history of the condition is based on a handful of families. Patient stratification by mutation type and functional effect, along with funding for preclinical models and a registry of affected individuals, would be needed before any treatment hypothesis could be tested.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
BMC Medical Genetics · 2017 · 49 citations · open access
Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters
AbstractBACKGROUND: Epileptic encephalopathies are a group of childhood epilepsies that display high phenotypic and genetic heterogeneity. The recent, extensive use of next-generation sequencing has identified a large number of genes in epileptic encephalopathies, including UBA5 in which biallelic mutations were first described as pathogenic in 2016 (Colin E et al., Am J Hum Genet 99(3):695-703, 2016. Muona M et al., Am J Hum Genet 99(3):683-694, 2016). UBA5 encodes an activating enzyme for a post-translational modification mechanism known as ufmylation, and is the first gene from the ufmylation pathway that is linked to disease. CASE PRESENTATION: We sequenced the genomes of two sisters with early-onset epileptic encephalopathy along with their unaffected parents in an attempt to find a genetic cause for their condition. The sisters, born in 2004 and 2006, presented with infantile spasms at six months of age, which later progressed to recurrent, treatment-resistant seizures. We detected a compound heterozygous genotype in UBA5 in the sisters, a genotype not seen elsewhere in an Icelandic reference set of 30,067 individuals nor in public databases. One of the mutations, c.684G > A, is a paternally inherited exonic splicing mutation, occuring at the last nucleotide of exon 7 of UBA5. The mutation is predicted to disrupt the splice site, resulting in loss-of-function of one allele of UBA5. The second mutation is a maternally inherited missense mutation, p.Ala371Thr, previously reported as pathogenic when in compound heterozygosity with a loss-of-function mutation in UBA5 and is believed to produce a hypomorphic allele. Supportive of this, we have identified three adult Icelanders homozygous for the p.Ala371Thr mutation who show no signs of neurological disease. CONCLUSIONS: We describe compound heterozygous mutations in the UBA5 gene in two sisters with early-onset epileptic encephalopathy. To our knowledge, this is the first description of mutations in UBA5 since the initial discovery that pathogenic biallelic variants in the gene cause early-onset epileptic encephalopathy. We further provide confirmatory evidence that p.Ala371Thr is a hypomorphic mutation, by presenting three adult homozygotes who show no signs of neurological disease.
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.
Journal of Child Neurology · 2023 · 6 citations · open access
Safety of Diazepam Nasal Spray in Pediatric Patients With Developmental Epileptic Encephalopathies: Results From a Long-term Phase 3 Safety Study
AbstractPediatric developmental epileptic encephalopathies are often refractory to treatment despite stable antiseizure therapy. The safety profile of diazepam nasal spray (Valtoco) as rescue therapy for seizure clusters was described in a long-term safety study. This post hoc analysis assessed safety and effectiveness within a subpopulation of patients with developmental epileptic encephalopathies. Of 163 treated patients, 64 were diagnosed with ≥1 pediatric developmental epileptic encephalopathy. Among the most common developmental epileptic encephalopathies were Rett syndrome (n = 16), Lennox-Gastaut syndrome (n = 9), and Dravet syndrome (n = 7). In the broad pediatric developmental epileptic encephalopathy group, 10.6% of seizure clusters were treated with a second dose, with similar proportions in the 3 individual encephalopathies. Across groups, treatment-emergent adverse event rates ranged from 66.7% to 100%. Only epistaxis (n = 2) was treatment-related and reported in >1 patient. In this long-term safety analysis in patients with developmental epileptic encephalopathies, diazepam nasal spray demonstrated a consistent safety profile, supporting its use in these hard-to-treat patients (ClinicalTrials.gov NCT02721069).
A Child with Epilepsy: Initial Presentation and Subsequent Course
AbstractPresented is the case of a child with epilepsy with dramatic evolution between the ages of 18 months and 3 years. Initially, the case is one of treatment-responsive focal epilepsy, but then evolves to treatment-resistant focal epilepsy with an epileptic encephalopathy. The case demonstrates the poorly understood entities of age-related changes in seizure suspectibility, seizure types, and drug responsiveness.
AbstractChildhood epilepsy is characterized by specific epilepsy syndromes that occur during each developmental age. These "age-dependent" epilepsy syndromes are clinically categorized into a self-limited epilepsy group with good prognosis and high prevalence rate and a pharmacoresistant epilepsy group with poor prognosis despite low prevalence rates. Many children develop pharmacoresistant epilepsy beginning in early infancy and progress to developmental epileptic encephalopathy, which is associated with intellectual, behavioral, and/or motor disabilities. These children do not show remission in epilepsy and are transitioned to the adult service and require comprehensive medical care.
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.
