DeCure for Intellectual disability, autosomal recessive 59
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for intellectual disability, autosomal recessive 59 — 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 moduleIntellectual disability, autosomal recessive 59 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 intellectual disability, autosomal recessive 59 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
inositol monophosphatase 1 (IMPA1) — IMPA1 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-oxidanylphenoxydrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6GIU · 1.39 Å · ligand [1-(4-oxidanylphenoxy)-1-phosphono-ethyl]phosphonic acid (L69). Experimental structure, not a prediction.
What the evidence adds up to
A missense mutation in MED23 (p. R617Q) was found to cosegregate with nonsyndromic autosomal recessive intellectual disability in one family. The mutation impaired the response of JUN and FOS immediate early genes to serum mitogens by altering the interaction between enhancer-bound transcription factors and Mediator. Transcriptional dysregulation of these genes was also observed in cells from patients with other neurological disorders linked to mutations in other Mediator subunits. The 2011 study proposed that altered immediate early gene expression might be a common molecular hallmark of cognitive deficit.
A 2014 homozygosity mapping study of 11 consanguineous Pakistani families multiplex for intellectual disability identified 45 potential homozygosity-by-descent regions across the families, later rationalised to 39. Two families shared an overlapping region on 7q11.21. In one family X-linkage appeared plausible. In one family no homozygosity-by-descent region was found, excluding autosomal recessive mutation as the likely cause. No copy-number variants segregating with the phenotype were detected. The authors stated they were proceeding with whole-exome sequencing to identify causative mutations within the identified regions.
A 2021 review noted that autosomal recessive intellectual disability accounts for most molecular bases in inbred populations, but that most published cohort genetic studies have revealed the important contribution of de novo variants. A 2022 paper on Bardet-Biedl Syndrome mouse models stated that there are limited pharmacological interventions for intellectual disability, partially due to poor understanding of the heterogeneous nature of the condition, and that there are limited mouse models of intellectual disability.
What is still missing: no drug has been tested in any clinical trial for autosomal recessive intellectual disability caused by MED23 mutation. No mouse model of MED23-related intellectual disability has been reported. No patient stratification strategy exists for this specific mutation. Funding for preclinical work and for developing animal models remains absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Science · 2011 · 118 citations
<i>MED23</i> Mutation Links Intellectual Disability to Dysregulation of Immediate Early Gene Expression
AbstractMED23 is a subunit of the Mediator complex, a key regulator of protein-coding gene expression. Here, we report a missense mutation (p. R617Q) in MED23 that cosegregates with nonsyndromic autosomal recessive intellectual disability. This mutation specifically impaired the response of JUN and FOS immediate early genes (IEGs) to serum mitogens by altering the interaction between enhancer-bound transcription factors (TCF4 and ELK1, respectively) and Mediator. Transcriptional dysregulation of these genes was also observed in cells derived from patients presenting with other neurological disorders linked to mutations in other Mediator subunits or proteins interacting with MED. These findings highlight the crucial role of Mediator in brain development and functioning and suggest that altered IEG expression might be a common molecular hallmark of cognitive deficit.
Homozygosity mapping of autosomal recessive intellectual disability loci in 11 consanguineous Pakistani families
AbstractBACKGROUND: Autosomal recessive intellectual disability (ID) is genetically heterogeneous and most of the genes causing it remain undiscovered. OBJECTIVE: We have ascertained 11 consanguineous families multiplex for IDs in order to identify new loci for autosomal recessive genes for non-syndromic ID, or to aid pinpointing mutations in known causative gene/loci. Methodology Microarray genotyping (Affymatrix 250K) was performed to identify homozygosity-by-descent (HBD) in all affected families. RESULTS: Analysis of genotypes revealed 45 potential HBD regions across the families, although these may be rationalised down to 39. Two families share an overlapping HBD region on 7q11.21. In one family, X-linkage also looks plausible, and a new ID gene near the centromere may be a likely cause. In one family, no HBD region was found, and thus we exclude autosomal recessive mutation as the likely cause in this family. Copy-number variation (CNV) was also performed and revealed no CNVs, homozygous or heterozygous, segregating with the phenotype. CONCLUSION: The homozygous loci identified in this study might harbour candidate genes for ID in these studied families. Therefore, we are proceeding with next-generation sequencing analysis of the families, using whole-exome approaches, and anticipate that this will identify the causative gene/mutation within the identified HBD regions for many of the families studied here.
Iowa Research Online (The University of Iowa) · 2022 · 0 citations · open access
Behavioral and brain phenotypes of mouse models of Bardet-Biedl Syndrome
AbstractIntellectual disability (ID) is one of the most common neurodevelopmental disorders, affecting 1% of the population globally. Clinically, ID is characterized by a deficit in intellectual functioning and adaptive functioning. There are limited pharmacological interventions for ID, partially due to a poor understanding of ID and the heterogeneous nature of ID In addition, there are limited mouse models of ID.
Majmaah Journal of Health Sciences · 2021 · 0 citations · open access
Review On Clinical And Molecular Genetics Of Autosomal Recessive Intellectual Disability
AbstractIntellectual disability (ID) is a relatively common phenotype with multiple etiologies. Recent progress in the genetics of ID greatly expanded our understanding of the biological defects underlying this clinical entity. While most published cohort genetic studies on ID revealed the important contribution of de novo (germline or postzygotic) variants, we focused in this study of autosomal recessive ID (ARID), that account for most of the molecular bases in ID cases in inbred populations. We discussed the current state of ARID from a clinical, molecular and genetics standpoints.
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.
