DeCure for Genetic developmental and epileptic encephalopathy
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for genetic developmental and epileptic encephalopathy — screening already-approved drugs against its 40-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleGenetic developmental and epileptic encephalopathy maps to a 40-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 genetic developmental and epileptic encephalopathy 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
neurotrophic receptor tyrosine kinase 2 (NTRK2) — NTRK2 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 4-methoxybenzyldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4AT5 · 1.71 Å · ligand 5-{3-methoxy-4-[(4-methoxybenzyl)oxy]benzyl}pyrimidine-2,4-diamine (MUJ). Experimental structure, not a prediction.
What the evidence adds up to
Developmental and epileptic encephalopathies are a heterogeneous group of disorders defined by early-onset, often drug-resistant seizures and developmental impairment that tends to worsen as a consequence of epilepsy. Genetic causes involve mutations in many genes affecting cell migration, neuronal excitability, and synaptic transmission. The overall prognosis is generally poor. No single drug or intervention is reported as uniformly effective across the genetic subtypes.
The abstracts describe the landscape of known genetic defects and the phenotypic continuum of these conditions, but they do not report any clinical trial results with specific response rates or survival data for any drug. One 2024 review notes that current therapeutic strategies include pharmacological treatments, nonpharmacological interventions, and emerging therapies such as gene and stem cell therapy, while also stating that significant challenges and limitations remain. Another 2022 review mentions that functional studies and clinical trials have explored the efficacy of different treatments, but provides no concrete numerical outcomes.
No abstract provides evidence of efficacy for any named drug in treating developmental and epileptic encephalopathy. The reviews consistently emphasise genetic heterogeneity and the need for better understanding of pathogenic mechanisms. The 2024 review explicitly identifies research gaps and calls for ongoing research and innovation.
What is still missing are large, genetically stratified clinical trials that report response rates and survival for specific mutations. The heterogeneity of the condition means that without patient stratification by genotype, no drug can be shown to work across the group. Funding for such stratified trials and for the development of mutation-specific therapies remains insufficient.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Physiological Reviews · 2022 · 182 citations · open access
Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum
AbstractDevelopmental and epileptic encephalopathies (DEEs) are a heterogeneous group of disorders characterized by early-onset, often severe epileptic seizures and EEG abnormalities on a background of developmental impairment that tends to worsen as a consequence of epilepsy. DEEs may result from both nongenetic and genetic etiologies. Genetic DEEs have been associated with mutations in many genes involved in different functions including cell migration, proliferation, and organization, neuronal excitability, and synapse transmission and plasticity. Functional studies performed in different animal models and clinical trials on patients have contributed to elucidate pathophysiological mechanisms underlying many DEEs and have explored the efficacy of different treatments. Here, we provide an extensive review of the phenotypic spectrum included in the DEEs and of the genetic determinants and pathophysiological mechanisms underlying these conditions. We also provide a brief overview of the most effective treatment now available and of the emerging therapeutic approaches.
Current Opinion in Neurology · 2013 · 19 citations
Pediatric epilepsy genetics
AbstractPURPOSE OF REVIEW: Genetic epilepsies in childhood are a complex group of disorders, with heterogeneous etiologies and clinicopathologic features. This review focuses on primary genetic epilepsies, which may have variable neuropsychiatric comorbidities, but usually have no underlying gross neuropathology or evident metabolic disturbance. Epilepsy due to inherited metabolic diseases, chromosomal abnormalities, phakomatoses, or malformations of cortical development is reviewed elsewhere. RECENT FINDINGS: The use of high-throughput approaches to sequence DNA and to detect copy number variants is revealing a landscape of mutations in genetic epilepsies, affecting a variety of genes involved in neuronal excitability, synaptic transmission, neuronal metabolism, or network development. SUMMARY: A number of distinct clinical syndromes of pediatric genetic epilepsy have been described and linked to specific gene defects. Phenotypes may include, in addition to epilepsy, variable degrees of intellectual disability, elements of autism spectrum disorders, other psychiatric disorders, and motor impairment. In some cases, these comorbidities derive from uncontrolled seizure activity (epileptic encephalopathies), but in other cases they are direct, multifaceted consequences of global brain dysfunction. Mutations may be de novo, or, when inherited, show reduced penetrance and variable expressivity. Understanding the genetics of these conditions will improve diagnosis, reveal pathogenic mechanisms, and eventually lead to better treatment.
Frontiers in Neurology · 2021 · 3 citations · open access
Genomic Investigation of Infantile and Childhood Epileptic Encephalopathies in Kazakhstan: An Urgent Priority
AbstractObjectives: Infantile and childhood epileptic encephalopathies are a group of severe epilepsies that begin within the first year of life and often portend increased morbidity. Many of them are genetically determined. The medical strategy for their management depends on the genetic cause. There are no facilities for genetic testing of children in Kazakhstan but we have a collection of data with already defined genes responsible for clinical presentations. Methods: We analyzed children with epileptic encephalopathies that began in the first 3 years of life and were accompanied by a delay/arrest of intellectual development, in the absence of structural changes in the brain. Such patients were recommended to undergo genetic testing using epileptic genetic panels in laboratories in different countries. Results: We observed 350 infants with clinical presentation of epileptic encephalopathies. 4.3% of them followed our recommendations and underwent genetic testing privately. In total 12/15 children became eligible for targeted treatment, 3/15 were likely to have non-epileptic stereotypies/movements, 2/15 were unlikely to respond to any therapy and all had a high chance of intellectual disability, behavioral and social communication disorders. Conclusion: The genetic results of 15/350 (4.3% of patients) have demonstrated the potential and enormous impact from gene panel analysis in management of epileptic encephalopathy. Availability of genetic testing within the country will improve management of children with genetic epilepsies and help to create a local database of pathogenic variants.
Dynamic electro‐clinical features in Guanidinoacetate N‐methyltransferase deficiency: A familial case series
AbstractGuanidinoacetate N-methyltransferase deficiency is an inborn error of creatine metabolism, responsible for the absent conversion of guanidinoacetic acid into creatine, resulting in cerebral creatine deficit. It could present a variety of symptoms such as neurodevelopmental delay, epilepsy, movement disorder (ataxia, dystonia, and chorea), and behavioral disturbances. After intellectual disability, epilepsy is the second most frequent expression of the disorder, usually arising during infancy with febrile seizures that are typically followed by generalized seizures and electroencephalographic anomalies. Herein, we describe three siblings with the same homozygous truncating variant in GAMT, all of whom showed significant global developmental delay during early infancy. The eldest two developed initially neglected atypical absences, preceded by focal motor seizures in the older brother, with complete remission with antiseizure medications and dietary treatment. Despite seizure freedom, during follow-up, both developed overt focal epileptiform discharges that have persisted after 2 years of creatine supplementation. Neither seizures nor electroencephalographic abnormalities were noted in the youngest brother who took advantage of an earlier diagnosis and treatment. The dynamic electroclinical pattern we observed has never been reported beforehand. Further studies are needed to assess the long-term prognosis of epilepsy in patients who have introduced dietary treatment after the seizure onset. PLAIN LANGUAGE SUMMARY: GAMT deficiency is a rare genetic disorder that prevents the brain from getting enough creatine, leading to developmental delay, seizures, movement disorders, and behavior problems. This condition often starts in infancy with seizures in fever and can be partially limited by creatine supplementation. In this paper, we present three siblings with the same mutation. The older two had seizures that improved with treatment, but their brain activity remained abnormal. The youngest, diagnosed and treated earlier with supplementation, did not develop epilepsy. More research is needed to understand electro-clinical features of this condition and the long-term effects of early or late dietary treatment.
DOAJ (DOAJ: Directory of Open Access Journals) · 2024 · 0 citations
Research progress on developmental and epileptic encephalopathy
AbstractDevelopmental and epileptic encephalopathy (DEE) is a group of heterogeneous disorders characterized by drug-resistant seizures and neurodevelopmental delay, which can hinder brain development and lead to severe cognitive, behavioral, and motor impairments. DEE is mainly driven by genetic factors, typically with an onset in infancy or early childhood and generally with an overall poor prognosis. This article provides a review of the definition, epilepsy syndromes, genetic etiology, and precision treatment of DEE.
A Comprehensive Review on Current Insights Into Epileptic Encephalopathy: Pathogenesis and Therapeutic Strategies
AbstractEpileptic encephalopathy (EE) represents a challenging group of disorders characterized by severe epilepsy and significant cognitive, behavioral, and neurological impairments. This comprehensive review aims to elucidate the current insights into the pathogenesis and therapeutic strategies for these disorders. Pathogenesis involves a complex interplay of genetic factors, neurobiological mechanisms, and environmental influences that contribute to the severity and progression of symptoms. Clinical manifestations are diverse, encompassing various seizure types, cognitive and behavioral impairments, and developmental delays. Current therapeutic strategies include pharmacological treatments, nonpharmacological interventions, and emerging therapies such as gene and stem cell therapy. Despite advancements, significant challenges and limitations remain, highlighting the need for ongoing research and innovation. This review synthesizes existing knowledge, identifies research gaps, and proposes future directions, emphasizing the potential for personalized medicine to improve patient outcomes and quality of life.
Modern pediatrics Ukraine · 2021 · 0 citations · open access
On the study of seizures in newborns and early age children (features of diagnosis and clinical and genetic characteristics of epileptic encephalopathies)
AbstractThe article is devoted to the urgent problem of neonatology and pediatric neurology — seizures in newborns and young children. In the work, a short review of the clinical and genetic characteristics of monogenic epilepsy is presented, in particular, the main attention is paid to the variants that begin in neonatal and early childhood. It has been shown that a significant number of epileptic encephalopathies are caused by mutations in genes whose protein products form voltage-dependent (sodium and potassium), ligan(dependent (γ-aminobutyric acid — GABA) channels, the functioning of which ensures the passage of a nerve impulse in neurons of the cerebral cortex. The necessity of including the molecular genetic methods into the algorithm for examining a child with epilepsy, in particular with epileptic encephalopathy, is emphasized. It is noted that congenital metabolic disorders are one of the etiological reasons for the development of epileptic seizures in children, in particular in newborns and young children. It was shown that congenital metabolic disorders have phenotypic manifestations of epileptic encephalopathy. Some curable metabolic defects that are accompanied by seizures, their diagnosis and timely treatment are described. No conflict of interest was declared by the authors. Key words: newborn, epilepsy, epileptic encephalopathy, diagnosis, genetic examination, metabolic defects, review.
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.
