DeCure for Developmental and epileptic encephalopathy, 31B
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for developmental and epileptic encephalopathy, 31B — 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 moduleDevelopmental and epileptic encephalopathy, 31B 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 developmental and epileptic encephalopathy, 31b 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
CDKN1A interacting zinc finger protein 1 (CIZ1) — CIZ1 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 7X39 · 2.85 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Two sisters with early-onset epileptic encephalopathy, born in 2004 and 2006, carried compound heterozygous mutations in UBA5. One mutation, c.684G>A, was a paternally inherited exonic splicing mutation predicted to disrupt the splice site and cause loss of function of one allele. The second, p.Ala371Thr, was a maternally inherited missense mutation 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 the interpretation that p.Ala371Thr is a hypomorphic allele. The sisters presented with infantile spasms at six months of age that progressed to recurrent, treatment-resistant seizures. The compound heterozygous genotype was not found in an Icelandic reference set of 30,067 individuals or in public databases.
A separate abstract describes RHOBTB2-related developmental and epileptic encephalopathy 64, caused by de novo missense variants clustering in the BTB domains. That disorder is characterised by seizure onset in the first year of life, severe to profound intellectual disability, movement disorders, postnatal microcephaly, and nonspecific dysmorphic features. No therapeutic intervention for RHOBTB2-related DEE is reported in this abstract.
By August 2022, 105 genes had been associated with developmental and epileptic encephalopathy according to OMIM. No drug treatment, repurposed or otherwise, is tested or proposed in any of these abstracts. No survival data, response rates, or sample sizes beyond the two sisters and the three adult homozygotes are given. What is missing for any therapeutic development — whether for UBA5, RHOBTB2, or the broader set of DEE genes — is a candidate drug, a preclinical model, a trial design, and patient stratification strategies.
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.
Genetics in Medicine Open · 2024 · 1 citations · open access
O42: Development of an anti-sense oligonucleotide therapeutic targeting RhoBTB2-related epileptic encephalopathy
AbstractRHOBTB2 encodes a member of the atypical Rho GTPase containing a GTPase domain and two tandem BTB domains. The BTB domains are involved in interacting with the Cullin3-dependent ubiquitin ligase complex, mediating ubiquitination, and recruiting substrates to the complex. Pathogenic de novo missense variants clustering in the BTB domains were reported to cause autosomal dominant developmental and epileptic encephalopathy 64 [DEE64; OMIM 618004]. DEE64 is a neurodevelopmental disorder characterized by onset of seizures within the first year of life, severe to profound intellectual disability, movement disorders, postnatal microcephaly, and nonspecific dysmorphic features.
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.
