DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for intellectual disability, X-linked 19 — 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 19 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 19 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
ribosomal protein S6 kinase A3 (RPS6KA3) — RPS6KA3 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 2sdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4D9T · 2.4 Å · ligand methyl (2S)-3-{4-amino-7-[(1E)-3-hydroxyprop-1-en-1-yl]-5-(4-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-2-cyanopropanoate (0JG). Experimental structure, not a prediction.
What the evidence adds up to
X-linked intellectual disability accounts for over 10% of all intellectual disability cases, with a prevalence of 2.6 per 1,000 in the general population. Two thirds of X-linked cases are thought to be non-syndromic. Mutations in the IL1RAPL1 gene have been found in multiple families with non-syndromic X-linked intellectual disability; all published mutations predict loss of function of the protein. Two additional families with deletions of a portion of IL1RAPL1 were identified, giving rise to cognitive impairment along with some behavioural problems and mild dysmorphism. The aristaless-related homeobox (ARX) gene is one of the most frequently mutated X-linked intellectual disability genes, responsible for about 9.5% of X-linked cases. More than 110 mutations have been reported in ARX; the phenotype always involves intellectual disability and often includes epilepsy, infantile spasms, hand dystonia, lissencephaly, autism or dysarthria. ARX encodes a highly conserved protein with a role in the Wnt/β-catenin signalling pathway, and sequence alignment confirms its functional domains are highly conserved across species.
A review of X-linked copy number variants (CNVs) notes that chromosomal microaberrations are frequently found in patients with intellectual disability, and discusses the modifying effect of X chromosome inactivation on the phenotype of carriers of X-linked mutations. Interpretation of the clinical significance of X-linked CNVs remains a problem. One evolutionary genomics study found no evidence for a higher incidence of recent positive selection on X-linked intellectual disability genes compared to autosomal ones, nor a higher incidence on such genes overall versus control genes. However, X-linked intellectual disability genes inferred to be subject to recent positive selection were concentrated in the Rho GTP-ase pathway, a key signalling pathway in neural development.
No treatment trials are described in these abstracts. Outcome measures for core symptoms of intellectual disability are an unresolved problem: tools designed to assess intellectual and adaptive functioning have rarely been used as primary outcome measures, and further study is needed regarding their usefulness to measure change. The field lacks validated endpoints that can demonstrate an impact on core features of intellectual disability in treatment trials. What is still missing is the development and validation of appropriate outcome measures, funding for trials that test mechanism-modifying treatments in genetically defined subgroups, and patient stratification by specific gene mutations such as IL1RAPL1 or ARX rather than by broad diagnostic category.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
American Journal of Medical Genetics Part A · 2011 · 41 citations
Deletion of the immunoglobulin domain of <i>IL1RAPL1</i> results in nonsyndromic X‐linked intellectual disability associated with behavioral problems and mild dysmorphism
AbstractX-Linked intellectual disability accounts for a significant fraction of males with cognitive impairment. Many of these males present with a non-syndromic phenotype and presently mutations in 17 X-linked genes are associated with these patients. Mutations in IL1RAPL1 have been found in multiple families with non-syndromic X-linked intellectual disability. All of the published mutations predict loss of function of the protein. We have identified an additional two families with deletions of a portion of the gene that give rise to cognitive impairment, as well as some behavioral problems and mild dysmorphism. Our clinical findings better delineate the phenotypic spectrum associated with IL1RAPL1 mutations.
Cochrane Database of Systematic Reviews · 2013 · 39 citations · open access
Pharmacological interventions for self-injurious behaviour in adults with intellectual disabilities
AbstractBACKGROUND: Self-injurious behaviour among people with intellectual disability is relatively common and often persistent. Self-injurious behaviour continues to present a challenge to clinicians. It remains poorly understood and difficult to ameliorate despite advances in neurobiology and psychological therapies. There is a strong need for a better evidence base in prescribing and monitoring of drugs in this population, especially since none of the drugs are actually licensed for self-injurious behaviour. OBJECTIVES: To determine clinical effectiveness of pharmacological interventions in management of self-injurious behaviour in adults with intellectual disability. SEARCH METHODS: We searched the following databases on 19 February 2012: CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL, Science Citation Index, Social Science Citation Index, Conference Proceedings Citation Index - Science, Conference Proceedings Citation Index - Social Science and Humanities, ZETOC and WorldCat. We also searched ClinicalTrials.gov, ICTRP and the reference lists of included trials. SELECTION CRITERIA: We included randomised controlled trials that examined drug interventions versus placebo for self-injurious behaviour (SIB) in adults with intellectual disability. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias for each trial using a data extraction form. We present a narrative summary of the results is presented. We did not consider meta-analysis was appropriate due to differences in study designs, differences between interventions and heterogeneous outcome measures. MAIN RESULTS: We found five double-blind placebo-controlled trials that met our inclusion criteria. These trials assessed effectiveness and safety of drugs in a total of 50 people with intellectual disability demonstrating SIB. Four trials compared the effects of naltrexone versus placebo and one trial compared clomipramine versus placebo.One of the naltrexone versus placebo trials reported that naltrexone had clinically significant effects (≥ 33% reduction) on the daily rates of three of the four participants' most severe form of SIB and modest to substantial reductions in SIB for all participants; however, this study did not report on statistical significance. Another trial reported that naltrexone attenuated SIB in all four participants, with 25 mg and 50 mg doses producing a statistically significant decrease in SIB (P value < 0.05). Another trial (eight people) indicated that naltrexone administration was associated with significantly fewer days of high frequency self injury and significantly more days with low frequency self injury. Naltrexone had different effects depending on the form and location of self injury. Another trial with only 26 participants found that neither single-dose (100 mg) nor long-term (50 and 150 mg) naltrexone treatment had any therapeutic effect on SIB.Comparison of clomipramine versus placebo found no statistically significant benefit for any outcome measure, which included SIB rate and intensity, stereotypy and adverse events. However, it showed clinically significant improvement in the rate and intensity of SIB and stereotypy.There were very few noteworthy adverse events to report in any of the four trials in which these were reported.All trials were at high risk of bias, apart from one trial (Lewis 1996), which was probably at low risk of bias. The short period of follow-up was a significant drawback in the design of all five trials, as it did not allow long-term assessment of behaviour over time.We were unable to examine the efficacy of antidepressants other than clomipramine, antipsychotics, mood stabilisers or beta-blockers as we did not identify any relevant placebo-controlled trials. AUTHORS' CONCLUSIONS: There was weak evidence in included trials that any active drug was more effective than placebo for people with intellectual disability demonstrating SIB. Due to sparse data, an absence of power and statistical significance, and high risk of bias for four of the included trials, we are unable to reach any definite conclusions about the relative benefits of naltrexone or clomipramine compared to placebo.
American Journal on Intellectual and Developmental Disabilities · 2020 · 35 citations
Outcome Measures for Core Symptoms of Intellectual Disability: State of the Field
AbstractIntellectual disability (ID) is defined by impairments in intellectual and adaptive functioning. As such, tools designed to assess these domains would theoretically be ideal outcome measures for treatment trials targeting core symptoms of ID. However, measures of intellectual and adaptive functioning have rarely been used as primary outcome measures to date and further study is needed regarding their usefulness to measure change. This area of inquiry is important because promising, mechanism-modifying treatments for conditions leading to ID are being initiated. To show efficacy, these treatments need to demonstrate an impact on core features of ID. After reviewing literature on this topic, we suggest solutions to several problems outlined, including use of out-of-age-range testing, alternative metrics, and development of new measures.
Evolutionary Applications · 2009 · 11 citations · open access
Evolutionary genomics of human intellectual disability
AbstractPrevious studies have postulated that X-linked and autosomal genes underlying human intellectual disability may have also mediated the evolution of human cognition. We have conducted the first comprehensive assessment of the extent and patterns of positive Darwinian selection on intellectual disability genes in humans. We report three main findings. First, as noted in some previous reports, intellectual disability genes with primary functions in the central nervous system exhibit a significant concentration to the X chromosome. Second, there was no evidence for a higher incidence of recent positive selection on X-linked than autosomal intellectual disability genes, nor was there a higher incidence of selection on such genes overall, compared to sets of control genes. However, the X-linked intellectual disability genes inferred to be subject to recent positive selection were concentrated in the Rho GTP-ase pathway, a key signaling pathway in neural development and function. Third, among all intellectual disability genes, there was evidence for a higher incidence of recent positive selection on genes involved in DNA repair, but not for genes involved in other functions. These results provide evidence that alterations to genes in the Rho GTP-ase and DNA-repair pathways may play especially-important roles in the evolution of human cognition and vulnerability to genetically-based intellectual disability.
X-Linked CNV in Pathogenetics of Intellectual Disability
AbstractThe review considers monogenic and chromosomal mutations associated with X-linked intellectual disability. Peculiarities of the development of the clinical phenotype in cases of different mutations were described. Special attention is paid to X-linked CNVs (microdeletions and microduplications). Chromosomal microaberrations most frequently found in patients with intellectual disability are presented. A modifying effect of X chromosome inactivation on the phenotype of carriers of X-linked mutations is discussed. The problems of interpretation of the clinical significance of X-linked CNVs are considered.
Journal of genetics and molecular biology · 2019 · 4 citations
ARX gene with an impressive role in X-linked intellectual disability
AbstractIntellectual disability is the most common neurodevelopmental defect in the worldwide. X-linked intellectual disability (XLID) is the frequent form of intellectual disability which includes a heterogeneous group of inherited disorders emerging as various degrees of intellectual disabilities. XLID has a prevalence of 2.6 cases per 1,000 in the general population and accounts for over 10% of all cases of intellectual disability. Based on associated phenotypes, XLID is subdivided into syndromic (S-XLID) and non-syndromic (NS-XLID) forms; where two third of XLID cases are thought to be non-syndromic. Among the non-syndromic form, the aristalessrelated homeobox gene (ARX) gene is one of the ideal candidates to be evaluated in NS-XLID, since its mutations are responsible for about 9.5% of XLID cases. The ARX is located on the Xp22.13 genomic region and encodes a highly conserved protein with a considerable role in Wnt/β-catenin signaling pathway. Base on review literature, mutations in ARX gene has a particular influence on the critical processes associated with the brain development. Our results in bioinformatics study of molecular features, second and quaternary structures of ARX gene and also the phylogeny tree of ARX protein is showed that the ARX is a highly conserved protein with a substantial role in an important developmental pathway and its deficiency can cause irreversible defects, mainly in brain, that leads to the development of XLID as a common form of intellectual disability and also, the sequence alignment of this protein with other spices confirms that the functional domains of ARX protein are highly conserved, thus it has been predicted that the mutations of this gene is highly pathogenic. Alongside, we mainly focused to gather the data addressing the structural properties of ARX protein and bioinformatics assay of this protein to find the important role of ARX gene in the integrity of normal brain development.
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.
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.
