DeCure for Syndromic X-linked intellectual disability Lubs type
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for syndromic X-linked intellectual disability Lubs type — 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 moduleSyndromic X-linked intellectual disability Lubs type 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 syndromic x-linked intellectual disability lubs type 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
methyl-CpG binding protein 2 (MECP2) — MECP2 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 unxdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6OGK · 1.65 Å · ligand UNKNOWN ATOM OR ION (UNX). Experimental structure, not a prediction.
What the evidence adds up to
Fragile X syndrome, the most common inherited form of intellectual disability and autism, is caused by silencing of the FMR1 gene and loss of its product FMRP. A 2016 study found that FMRP normally binds the messenger RNA for bone morphogenetic protein type II receptor (BMPR2). When FMRP is absent, BMPR2 abundance increases, particularly a full-length isoform that activates LIM domain kinase 1 (LIMK1), a component of a noncanonical BMP signalling pathway that stimulates actin reorganisation and synapse formation. In both Drosophila and mouse models of fragile X syndrome, heterozygosity for BMPR2 rescued the morphological abnormalities in neurons. Postnatal pharmacological inhibition of LIMK1 had the same effect. In postmortem prefrontal cortex tissue from fragile X patients, the amount of full-length BMPR2 and a marker of LIMK1 activity was increased compared with healthy controls. The authors concluded that increased BMPR2-LIMK1 signalling is linked to fragile X syndrome and that this pathway is a putative therapeutic target.
X-linked intellectual disability (XLID) affects 1% to 3% of the population and accounts for over 10% of all intellectual disability cases, according to two review papers from 2013 and 2019. The 2019 review notes a prevalence of 2.6 cases per 1,000. XLID is subdivided into syndromic and non-syndromic forms; about two-thirds of cases are thought to be non-syndromic. Among non-syndromic XLID, mutations in the ARX gene are responsible for roughly 9.5% of cases. The ARX gene is located on Xp22.13 and encodes a highly conserved protein involved in the Wnt/β-catenin signalling pathway. The 2013 review covers a broader set of XLID proteins, including FMRP, MeCP2, CDKL5, Rho GTPase signalling molecules, and cell adhesion molecules, and discusses how mutations in these genes affect synapse structure and function.
No clinical trial data for any drug in syndromic XLID Lubs type specifically are presented in these abstracts. The 2016 study used only animal models and postmortem human tissue; it did not test any drug in living patients. The two review papers summarise genetic and molecular findings but do not report any therapeutic intervention. What is still missing is any clinical trial testing a BMPR2 or LIMK1 inhibitor in patients with fragile X syndrome or other forms of XLID, as well as patient stratification by specific genetic mutation, and funding for translational work that moves from animal models to human studies.
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 Signaling · 2016 · 68 citations · open access
Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome
AbstractEpigenetic silencing of fragile X mental retardation 1 (FMR1) causes fragile X syndrome (FXS), a common inherited form of intellectual disability and autism. FXS correlates with abnormal synapse and dendritic spine development, but the molecular link between the absence of the FMR1 product FMRP, an RNA binding protein, and the neuropathology is unclear. We found that the messenger RNA encoding bone morphogenetic protein type II receptor (BMPR2) is a target of FMRP. Depletion of FMRP increased BMPR2 abundance, especially that of the full-length isoform that bound and activated LIM domain kinase 1 (LIMK1), a component of the noncanonical BMP signal transduction pathway that stimulates actin reorganization to promote neurite outgrowth and synapse formation. Heterozygosity for BMPR2 rescued the morphological abnormalities in neurons both in Drosophila and in mouse models of FXS, as did the postnatal pharmacological inhibition of LIMK1 activity. Compared with postmortem prefrontal cortex tissue from healthy subjects, the amount of full-length BMPR2 and of a marker of LIMK1 activity was increased in this brain region from FXS patients. These findings suggest that increased BMPR2 signal transduction is linked to FXS and that the BMPR2-LIMK1 pathway is a putative therapeutic target in patients with FXS and possibly other forms of autism.
The Neurobiology of X-Linked Intellectual Disability
AbstractX-linked intellectual disability (XLID) affects 1% to 3% of the population. XLID subsumes several heterogeneous conditions, all of which are marked by cognitive impairment and reduced adaptive skills. XLID arises from mutations on the X chromosome; to date, 102 XLID genes have been identified. The proteins encoded by XLID genes are involved in higher brain functions, such as cognition, learning and memory, and their molecular role is the subject of intense investigation. Here, we review recent findings concerning a representative group of XLID proteins: the fragile X mental retardation protein; methyl-CpG-binding protein 2 and cyclin-dependent kinase-like 5 proteins, which are involved in Rett syndrome; the intracellular signaling molecules of the Rho guanosine triphosphatases family; and the class of cell adhesion molecules. We discuss how XLID gene mutations affect the structure and function of synapses.
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.
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.
