DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Cockayne syndrome type 2 — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCockayne syndrome type 2 maps to a 2-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 cockayne syndrome type 2 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
ERCC excision repair 8, CSA ubiquitin ligase complex subunit (ERCC8) — ERCC8 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 adpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8B3D · 2.6 Å · ligand ADENOSINE-5'-DIPHOSPHATE (ADP). Experimental structure, not a prediction.
What the evidence adds up to
In a cohort of 100 patients with Cockayne syndrome enrolled in a natural history study, 8 cases of acute hepatic failure after metronidazole administration were identified, representing 8% of the cohort. Three of those 8 cases were fatal, with death occurring 6 to 11 days after the first dose. Two of the fatal cases also developed acute neurologic deficit. No patient with Cockayne syndrome who received metronidazole in that cohort was observed to have done so without serious adverse effects. A separate 2020 report describes two further cases: a 2-year-old boy who died of acute liver failure 48 hours after starting metronidazole for gastroenteritis, and a 5-year-old boy who developed jaundice and drowsiness after metronidazole and amoxicillin for a dental infection but recovered with supportive care. The authors of the 2015 case series recommend that a diagnosis of Cockayne syndrome be considered an absolute contraindication to metronidazole.
Two patient-derived induced pluripotent stem cell lines, one from a patient with a severe form of Cockayne syndrome and one from a patient with a milder form, were used to generate neurospheres and cerebral organoids. RNA sequencing of CSB-deficient neurospheres showed upregulation of the VEGFA-VEGFR2 signalling pathway, vesicle-mediated transport, and head development compared to controls. In CSB-deficient cerebral organoids, downregulation of brain development, neuron projection development, and synaptic signalling was observed. Upregulation of steroid biosynthesis, particularly the cholesterol biosynthesis branch, was common to both neurospheres and organoids. The authors interpret these transcriptional changes as evidence that Cockayne syndrome involves not only neurodegeneration but also neurodevelopmental dysregulation.
What remains missing is any clinical trial testing a drug that might reverse or slow the neurodevelopmental or neurodegenerative process in Cockayne syndrome. The metronidazole data are a safety warning, not a treatment. No therapy has been shown to alter the course of the disease in patients. The organoid work identifies transcriptional targets — cholesterol biosynthesis, VEGFR2 signalling — but no drug has been tested against those targets in patients, and no funding for such a trial is described in these abstracts. Patient stratification by severity of CSB mutation may be necessary for any future trial, but that has not been done.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
PEDIATRICS · 2015 · 27 citations
Metronidazole Toxicity in Cockayne Syndrome: A Case Series
AbstractCockayne syndrome (CS) is a rare genetic disorder characterized by small stature, intellectual disability, and accelerated pathologic aging. Through the Cockayne Syndrome Natural History Study, we have identified 8 cases of acute hepatic failure after metronidazole administration (8% of our cohort), 3 of which were fatal. The interval between initial administration and death was 6 to 11 days. Two of these patients also experienced acute neurologic deficit. Both hepatotoxicity and acute neurologic deficit have been reported previously as extremely rare adverse events after metronidazole administration. However, we have not identified any patients with CS who have received metronidazole without serious adverse effects. We recommend that a diagnosis of CS be considered an absolute contraindication to the use of metronidazole.
Response of Motor Complications in Cockayne Syndrome to Carbidopa-Levodopa
AbstractBACKGROUND: Gait difficulties, tremors, and coordination difficulties are common features of Cockayne syndrome that are consequences of leukodystrophy, cerebellar atrophy, and demyelinating neuropathy, but no pharmacotherapy for these disabling symptoms is available. OBJECTIVE: To determine whether carbidopa-levodopa relieves tremors and other motor complications of Cockayne syndrome. DESIGN: Mutation analysis and case report study. SETTING: Hospital clinic and genetics research laboratory. Patients We studied 3 patients with Cockayne syndrome, a rare autosomal recessive neurodegenerative disorder for which no known treatments are available. Intervention Carbidopa-levodopa therapy. MAIN OUTCOME MEASURES: Status of tremors, ability to perform daily tasks, serial physical examinations, and results of handwriting samples. RESULTS: All 3 patients had a clear reduction in tremors and improvements in handwriting and manipulation of utensils and cups. CONCLUSIONS: Patients with Cockayne syndrome should be evaluated carefully for movement disorders. A clinical trial should be considered to evaluate this therapy further.
Cockayne Syndrome Patient iPSC-Derived Brain Organoids and Neurospheres Show Early Transcriptional Dysregulation of Biological Processes Associated with Brain Development and Metabolism
AbstractCockayne syndrome (CS) is a rare hereditary autosomal recessive disorder primarily caused by mutations in Cockayne syndrome protein A (CSA) or B (CSB). While many of the functions of CSB have been at least partially elucidated, little is known about the actual developmental dysregulation in this devasting disorder. Of particular interest is the regulation of cerebral development as the most debilitating symptoms are of neurological nature. We generated neurospheres and cerebral organoids utilizing Cockayne syndrome B protein (CSB)-deficient induced pluripotent stem cells derived from two patients with distinct severity levels of CS and healthy controls. The transcriptome of both developmental timepoints was explored using RNA-Seq and bioinformatic analysis to identify dysregulated biological processes common to both patients with CS in comparison to the control. CSB-deficient neurospheres displayed upregulation of the VEGFA-VEGFR2 signalling pathway, vesicle-mediated transport and head development. CSB-deficient cerebral organoids exhibited downregulation of brain development, neuron projection development and synaptic signalling. We further identified the upregulation of steroid biosynthesis as common to both timepoints, in particular the upregulation of the cholesterol biosynthesis branch. Our results provide insights into the neurodevelopmental dysregulation in patients with CS and strengthen the theory that CS is not only a neurodegenerative but also a neurodevelopmental disorder.
Journal of Computer Assisted Tomography · 1982 · 12 citations
Cockayne Syndrome
AbstractThe diagnosis of Cockayne syndrome was established with the aid of cranial computed tomography (CT) in a child with growth deficiency, mental retardation, and neurologic findings which are typical for this rare childhood disorder. Calcification of basal ganglia and hydrocephalus ex vacuo are neuropathologic characteristics of Cockayne syndrome which may be present on CT as early as 3 years of age.
Case Reports in Pediatrics · 2020 · 6 citations · open access
Hepatic Failure following Metronidazole in Children with Cockayne Syndrome
AbstractCockayne syndrome is an uncommon autosomal recessive disease characterized by microcephaly, abnormal growth, and pathologic premature aging. The purpose of this report is to evaluate liver failure in children with Cockayne syndrome following metronidazole administration. The first case was a 2-year-old boy with Cockayne syndrome. He had been treated with metronidazole for gastroenteritis. 48 hours after treatment initiation, he was hospitalized due to jaundice, intractable vomiting, and agitation. Unfortunately, he died of acute liver failure. The second case was a 5-year-old boy with Cockayne syndrome as well, who had been treated with amoxicillin and metronidazole for a dental infection. He developed jaundice, drowsiness, lethargy, and anorexia after treatment. At hospital, the child received supportive treatment, and his general condition gradually improved. The liver enzyme levels decreased. He was finally discharged in good general condition. The mortality after metronidazole consumption in patients with Cockayne syndrome due to liver failure is very high. The awareness of the dangers of using metronidazole in these patients is valuable.
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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