DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Costello syndrome — screening already-approved drugs against its 34-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCostello syndrome maps to a 34-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 costello syndrome 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
mitogen-activated protein kinase 1 (MAPK1) — MAPK1 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 2~{s}drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8AOJ · 1.12 Å · ligand 1-[(2~{S})-2-(5-methyl-3-pyridin-4-yl-1~{H}-pyrazol-4-yl)pyrrolidin-1-yl]propan-1-one (N8L). Experimental structure, not a prediction.
What the evidence adds up to
Costello syndrome is caused by activating germline point mutations in HRAS, leading to increased signalling through the Ras-mitogen-activated protein kinase pathway. The disorder involves characteristic craniofacial features, failure to thrive, developmental delay, cardiac and skeletal anomalies, and a predisposition to benign and malignant neoplasia. Neurological abnormalities are not rare: ventricular dilatation is observed in more than 40% of cases, and brain atrophy, Chiari malformation and syringomyelia have also been reported. Two unrelated patients, a 5-year-old girl and a 3-year-old boy, both had coarse face, redundant or loose skin on hands and feet, curly hair, oral motor apraxia, and severe growth and psychomotor retardation; both had repeatedly high urine sialic acid levels, though the meaning of this biochemical abnormality remains unclear.
No drug treatment for the syndrome itself is described in these abstracts. One case report describes a girl with Costello syndrome and documented growth hormone deficiency who was treated with recombinant human growth hormone for almost four years. The authors state that growth hormone treatment can be considered in cases of documented deficiency, but only under close oncologic and cardiologic supervision. No other pharmacological interventions are mentioned.
The abstracts provide no data from controlled trials, no response rates, and no survival figures. The evidence is limited to case reports, a review of neurological findings, and the genetic discovery that HRAS mutations are causative. What is missing is any clinical trial of a targeted therapy, any attempt to inhibit the overactive Ras-MAPK pathway in patients, and any systematic data on whether growth hormone or any other agent alters the natural history of the condition. Patient stratification by specific HRAS mutation, tumour risk, or cardiac status has not been tested in a treatment trial. Funding for preclinical drug screening or for a small pilot trial of a Ras pathway inhibitor has not been reported.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Clinical Genetics · 2007 · 110 citations · open access
<i>HRAS </i>and the Costello syndrome
AbstractCostello syndrome (CS) is a complex developmental disorder involving characteristic craniofacial features, failure to thrive, developmental delay, cardiac and skeletal anomalies and a predisposition to develop neoplasia, both benign and malignant. CS is caused by activating germline mutations in HRAS and belongs to an exciting class of genetic syndromes that are caused by perturbation of function through the Ras pathway. Some of these other syndromes include Noonan syndrome, LEOPARD syndrome, neurofibromatosis 1 and cardio-facio-cutaneous syndrome. Ras is a critical signaling hub in the cell and is activated by receptor tyrosine kinases, G-protein-coupled receptors, cytokine receptors and extracellular matrix receptors. The downstream effectors of Ras are many and control vital cellular functions including cell cycle progression, cell survival, motility, transcription, translation and membrane trafficking. Understanding the genetic etiology of CS is the first step in gaining insight to the role Ras plays in human development, cellular signaling and cancer pathogenesis.
American Journal of Medical Genetics Part A · 2003 · 60 citations · open access
Costello syndrome and neurological abnormalities
AbstractCostello syndrome is a rare but increasingly recognized syndrome of unknown etiology. Neurological abnormalities are not rare in this syndrome and consist of structural and electrophysiological disorders. Ventricular dilatation is observed in more than 40% of cases. Other reported cerebral anomalies are brain atrophy, Chiari malformation and syringomyelia. Although there is insufficient data to propose strict guidelines, it seams reasonnable to have a low threshold for neuroimaging, in general, and particularly when neurologic signs or symptoms are present. Screening including cerebral MRI and EEG should be proposed after a diagnosis of Costello syndrome. The frequency of testing in such children should be guided by neurological follow-up.
Current Opinion in Pediatrics · 2007 · 56 citations
Costello syndrome and related disorders
AbstractPURPOSE OF REVIEW: Costello syndrome is a rare congenital disorder affecting multiple organ systems, encompassing severe failure to thrive, cardiac anomalies including hypertrophic cardiomyopathy and atrial tachycardia, tumor predisposition, and cognitive impairment. Costello syndrome shares findings with cardio-facio-cutaneous syndrome and the diagnosis can be challenging. The discovery of gene mutations underlying these and other closely related disorders allows for molecular confirmation of a clinical diagnosis. RECENT FINDINGS: The identification of germline HRAS mutations in Costello syndrome, and mutations in BRAF, MEK1 and MEK2 in cardio-facio-cutaneous syndrome, uncovered the biologic mechanism for the shared phenotypic findings based on the close interaction of the gene products within the Ras-mitogen-activated protein kinase pathway. Changes in other genes encoding mitogen-activated protein kinase pathway proteins are responsible for Noonan syndrome and the KRAS mutation phenotype. SUMMARY: Costello syndrome is caused by heterozygous de-novo point mutations in HRAS, resulting in increased activation of the mitogen-activated protein kinase pathway. Despite their overlapping presentation, Costello syndrome and its related disorders are distinct, and the phenotypes become more distinctive with age. Molecular testing is available and a clinical diagnosis should be reconsidered if it is inconsistent with the molecular result.
American Journal of Medical Genetics · 1993 · 48 citations
Report on two patients with Costello syndrome and sialuria
AbstractWe report on 2 unrelated patients with Costello syndrome. The first is a 5-year-old girl with "coarse" face, nasal papillomata, redundant skin of feet and hands, hyperextensible hand and finger joints, curly hair, feeding problems due to oral motor apraxia, growth and psychomotor retardation. The second is a 3-year-old boy with "coarse" face, loose skin on hands and feet, curly hair, oral motor apraxia, severe growth and psychomotor retardation. In both patients urine sialic acid levels were found to be repeatedly high. The meaning of this biochemical abnormality is discussed.
The Italian Journal of Pediatrics/Italian journal of pediatrics · 2016 · 7 citations · open access
Recombinant growth hormone therapy in a girl with costello syndrome: a 4-year observation
AbstractBACKGROUND: Costello syndrome is a rare syndrome of multiple congenital anomalies. The typical clinical traits include dysmorphic craniofacial features, skin hyperpigmentation and excess, feeding difficulties leading to severe postnatal growth retardation, short stature, joint hypermobility, and delayed psychomotor development. Additionally, Costello syndrome may present with an increased incidence of congenital heart disease, hypertrophic cardiomyopathy, and increased risk of both benign and malignant tumors. Furthermore, cases of patients with endocrine disorders such as adrenal insufficiency and endogenous growth hormone deficiency have also been documented. CASE PRESENTATION: We present a patient with Costello syndrome who has been successfully treated with recombinant human growth hormone (rhGH) for almost 4 years. CONCLUSIONS: The possibility of growth hormone (GH) treatment can be considered in cases of documented GH deficiency in patients with Costello syndrome, but only under close oncologic and cardiologic supervision.
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.
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