DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for intellectual disability, X-linked 58 — 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, X-linked 58 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, x-linked 58 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
tetraspanin 7 (TSPAN7) — TSPAN7 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 9W2B · 5.87 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
The MRX78 family, a large pedigree with six affected males and seven affected females showing X-linked inheritance, was resolved by identifying a missense mutation (c.C2366T, p.A789V) in IQSEC2. This gene encodes a neuronal GDP-GTP exchange factor for Arf family GTPases and had been previously implicated in X-linked intellectual disability. Molecular modelling predicted that the A789V substitution inserts a larger side-chain into a hydrophobic pocket in the catalytic Sec7 domain, causing clashes with adjacent amino acids and disrupting local folding. Functional assays confirmed that the recombinant IQSEC2(A789V) protein could not catalyse GDP-GTP exchange on Arf6 as efficiently as the wild-type protein.
A systematic review of physical activity correlates in people with intellectual disability, covering 26,456 participants, found only three consistent correlates, all in adults. Older age was associated with decreased physical activity in 7 of 11 studies (64%), more severe intellectual disability in 9 of 9 studies (100%), and the presence of physical mobility problems in 3 of 4 studies (75%). No consistent correlates were identified for children, adolescents, or older adults.
One review from 2011 stated that intellectual disability was considered an immutable condition and that current medical practices aimed only at relieving symptoms, not altering underlying cognitive deficits. It noted that scientific advancements had raised the possibility that intellectual disability might become treatable, citing fragile X syndrome as a potential benchmark for drug discovery. Another 2016 review summarised mutations in the ARX gene, one of the most frequently mutated X-linked intellectual disability genes after FMR1 and MECP2, noting that more than 110 mutations had been reported and that the phenotype always involves intellectual disability and often epilepsy, infantile spasms, hand dystonia, lissencephaly, autism, or dysarthria.
A 2020 study evaluated expressive language sampling as a source of outcome measures for treatment studies in fragile X syndrome, enrolling 106 individuals aged 6 to 23 years with IQs within the range of intellectual disability. The study addressed feasibility, practice effects, test-retest reliability, and construct validity for the full sample and for subgroups defined by age, IQ, and autism spectrum disorder status. What remains missing for the specific condition of X-linked intellectual disability 58 due to IQSEC2 mutation is any clinical trial data, any tested intervention, and any validated outcome measure tailored to this mutation. Funding for natural history studies and for development of mutation-specific outcome measures, as well as trial designs that account for the wide variability in severity and the small number of affected individuals, are still 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.
Frontiers in Molecular Neuroscience · 2016 · 27 citations · open access
Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 Family
AbstractDisease gene discovery in neurodevelopmental disorders, including X-linked intellectual disability (XLID) has recently been accelerated by next-generation DNA sequencing approaches. To date, more than 100 human X chromosome genes involved in neuronal signaling pathways and networks implicated in cognitive function have been identified. Despite these advances, the mutations underlying disease in a large number of XLID families remained unresolved. We report the resolution of MRX78, a large family with six affected males and seven affected females, showing X-linked inheritance. Although a previous linkage study had mapped the locus to the short arm of chromosome X (Xp11.4-p11.23), this region contained too many candidate genes to be analyzed using conventional approaches. However, our X-chromosome exome resequencing, bioinformatics analysis and inheritance testing revealed a missense mutation (c.C2366T, p.A789V) in IQSEC2, encoding a neuronal GDP-GTP exchange factor for Arf family GTPases (ArfGEF) previously implicated in XLID. Molecular modeling of IQSEC2 revealed that the A789V substitution results in the insertion of a larger side-chain into a hydrophobic pocket in the catalytic Sec7 domain of IQSEC2. The A789V change is predicted to result in numerous clashes with adjacent amino acids and disruption of local folding of the Sec7 domain. Consistent with this finding, functional assays revealed that recombinant IQSEC2(A789V) was not able to catalyze GDP-GTP exchange on Arf6 as efficiently as wild-type IQSEC2. Taken together, these results strongly suggest that the A789V mutation in IQSEC2 is the underlying cause of XLID in the MRX78 family.
Disability and Rehabilitation · 2021 · 26 citations
Physical activity correlates in children and adolescents, adults, and older adults with an intellectual disability: a systematic review
AbstractPURPOSE: Understanding enablers of and barriers for physical activity (PA) participation in people with intellectual disability (ID) is an essential first step to develop effective interventions. This systematic review examined correlates of PA across the socio-ecological model (i.e., intra-personal, inter-personal, environmental and policy level) in people with ID across the lifespan. MATERIAL AND METHODS: Major electronic databases were searched from inception until 15 February 2021. Keywords included "physical activity" or "exercise" and "intellectual disability" or "mental retardation." A summary coding was used to analyze the data for adolescents (<18 years), adults (18 < 50 years), and older adults (50≤ years). RESULTS: = 26,456), only three consistent (i.e., reported in four or more studies) correlates were identified. In adults, older age (7/11, 64%), more severe ID (9/9, 100%) and the presence of physical mobility problems (3/4, 75%) were associated with decreased PA. From 38 correlates identified, no consistent correlates were identified for children and adolescents and older people. CONCLUSIONS: Despite the abundance of evidence of the PA benefits for people with ID, we only found consistent evidence for three correlates reliably being related to PA in adults with ID. More research, particularly among young and older people is urgently needed.IMPLICATIONS FOR REHABILITATIONMore severe intellectual disability is an important barrier for being active in adults with intellectual disability.Presence of physical health problems is an important barrier for being active in adults with intellectual disability.
ACS Chemical Neuroscience · 2011 · 19 citations · open access
Fragile X Syndrome: An Update on Developing Treatment Modalities
AbstractIntellectual disability (ID; mental retardation) is considered an immutable condition. Current medical practices are aimed at relieving symptoms and not at altering the underlying cognitive deficits. Scientific advancements from the past decade have led to the exciting possibility that ID may now be treatable. Moreover, pharmaceutical therapies targeting the most common form of inherited ID, Fragile X syndrome (FXS), may become the new benchmark for central nervous system (CNS) drug discovery: seeking cures for neurodevelopmental disorders.
Oxford University Press eBooks · 2016 · 3 citations
Developmental Abnormalities Due to Mutations in the Aristaless-Related Homeobox Gene
AbstractAbstract Intellectual disability is a broad spectrum of neurodevelopmental disorders of the brain that combined affect approximately one in 50 individuals worldwide. X-linked intellectual disabilities represent a group of disorders where mutations arise on the X-chromosome. XLID is clinically complex and genetically heterogeneous. In excess of 100 genes are currently known. One of the most frequently mutated XLID genes (after e.g. FMR1 or MECP2) is the Aristaless related homeobox (ARX) gene. More than 110 mutations have been reported in ARX. The phenotype always involves intellectual disability and often also epilepsy, infantile spasms, hand dystonia, lissencephaly, autism or dysarthria. This chapter summarizes currently known mutations in ARX and their clinical manifestations and explores what is known about the underlying molecular and cellular mechanisms.
Expressive language sampling as a source of outcome measures for treatment studies in fragile X syndrome: feasibility, practice effects, test-retest reliability, and construct validity
AbstractAbstract Background The evaluation of treatment efficacy for individuals with fragile X syndrome (FXS) or intellectual disability (ID) more generally has been hampered by the lack of adequate outcome measures. We evaluated expressive language sampling (ELS) as a procedure for generating outcome measures for treatment research in FXS. We addressed: (a) feasibility, (b) practice effects over two administrations, (c) test-retest reliability over the repeated administrations, and (d) construct validity. We addressed these issues for the full sample as well as for subgroups defined by age, IQ, and ASD status. Methods Participants were 106 individuals with FXS between ages 6 and 23 years who had IQs within the range of intellectual disability (IQ
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.
