DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for leukodystrophy, hypomyelinating, 20 — 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 moduleLeukodystrophy, hypomyelinating, 20 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 leukodystrophy, hypomyelinating, 20 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
2',3'-cyclic nucleotide 3' phosphodiesterase (CNP) — CNP 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 1WOJ · 1.8 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Two unrelated males with de novo missense variants in EIF2AK2 (c.290C>T, p.Ser97Phe in proband 1; c.326C>T, p.Ala109Val in proband 2) presented in the first year of life with seizures and developmental delay. Common findings included horizontal or pendular nystagmus in infancy, axial hypotonia, appendicular hypertonia, spasticity, and episodic neurologic regression triggered by febrile viral illnesses. MRI showed severely delayed myelination in infancy; a hypomyelinating pattern was confirmed at age 4 years in proband 1 and at 13 months in proband 2. Neither PLP1 copy number variants nor pathogenic single nucleotide variants were found by chromosomal microarray or trio exome sequencing, leading to reanalysis that identified the EIF2AK2 variants. The authors conclude that autosomal dominant EIF2AK2-related leukoencephalopathy should be considered in the differential diagnosis for Pelizaeus-Merzbacher disease and other hypomyelinating leukodystrophies, and that a history of developmental regression with febrile illness may help distinguish it.
A 2012 case report describes one adult male diagnosed with cerebral palsy in infancy who later showed progressive neurological deterioration. Based on clinical presentation, MRI findings, and unremarkable laboratory and genetic tests, he was diagnosed with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). Mild slowed conduction velocities of sensory and motor peripheral nerves were found. Baclofen and Leucovorin were started as an attempt to improve symptoms and delay further deterioration. The authors note that cases reported with H-ABC have typical MRI features, are sporadic, and that clinical laboratory and genetic tests are all unremarkable. They also note that some cases reported in the literature had improvement of symptoms after symptomatic treatment was started.
A 2023 review states that hypomyelinating leukodystrophies are congenital rare diseases for which responsible genes have been identified in recent studies. It describes genetic mutations that cause protein misfolding, protein dysfunction, or mislocalisation associated with HLD, and states that insight into these pathways can provide new findings for clinical treatments. A 2002 review defines leukodystrophy as progressive diseases of myelin in which a molecular abnormality causes metabolic defects in myelin sheaths or myelin-forming cells, resulting in confluent destruction or failed development of central white matter.
No drug has been tested in a controlled trial for any of these specific genetic forms of hypomyelinating leukodystrophy. The 2012 case report of one patient given baclofen and leucovorin is anecdotal and does not report objective outcomes. What is missing is systematic natural history data for the EIF2AK2-related disorder, any preclinical model work testing specific compounds, and a trial design that accounts for the episodic regression pattern and the small number of patients available for enrolment.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Neurology Genetics · 2020 · 18 citations · open access
<i>EIF2AK2</i> -related Neurodevelopmental Disorder With Leukoencephalopathy, Developmental Delay, and Episodic Neurologic Regression Mimics Pelizaeus-Merzbacher Disease
Abstract<h3>Objective</h3> To demonstrate that de novo missense single nucleotide variants (SNVs) in <i>EIF2AK2</i> cause a neurodevelopmental disorder with leukoencephalopathy resembling Pelizaeus-Merzbacher disease (PMD). <h3>Methods</h3> A retrospective chart review was performed of 2 unrelated males evaluated at a single institution with de novo <i>EIF2AK2</i> SNVs identified by clinical exome sequencing (ES). Clinical and radiographic data were reviewed and summarized. <h3>Results</h3> Both individuals presented in the first year of life with concern for seizures and developmental delay. Common clinical findings included horizontal and/or pendular nystagmus during infancy, axial hypotonia, appendicular hypertonia, spasticity, and episodic neurologic regression with febrile viral illnesses. MRI of the brain demonstrated severely delayed myelination in infancy. A hypomyelinating pattern was confirmed on serial imaging at age 4 years for proband 1. In proband 2, repeat imaging at age 13 months confirmed persistent delayed myelination. These clinical and radiographic features led to a strong suspicion of PMD. However, neither <i>PLP1</i> copy number variants nor pathogenic SNVs were detected by chromosomal microarray and trio ES, respectively. Reanalysis of trio ES identified heterozygous de novo <i>EIF2AK2</i> missense variant c.290C>T (p.Ser97Phe) in proband 1 and c.326C>T (p.Ala109Val) in proband 2. <h3>Conclusions</h3> The autosomal dominant <i>EIF2AK2</i>-related leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome should be considered in the differential diagnosis for PMD and other hypomyelinating leukodystrophies (HLDs). A characteristic history of developmental regression with febrile illnesses may help distinguish it from other HLDs.
Neurology International · 2023 · 15 citations · open access
Molecular Pathogenic Mechanisms of Hypomyelinating Leukodystrophies (HLDs)
AbstractHypomyelinating leukodystrophies (HLDs) represent a group of congenital rare diseases for which the responsible genes have been identified in recent studies. In this review, we briefly describe the genetic/molecular mechanisms underlying the pathogenesis of HLD and the normal cellular functions of the related genes and proteins. An increasing number of studies have reported genetic mutations that cause protein misfolding, protein dysfunction, and/or mislocalization associated with HLD. Insight into the mechanisms of these pathways can provide new findings for the clinical treatments of HLD.
An Adult Patient with Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum Misdiagnosed as Cerebral Palsy (P03.137)
AbstractObjective: Prompt proper diagnosis of hypomyelination disorders will facilitate early symptomatic treatment that could improve the quality of life of these individuals, as well as family orientation about prognosis and genetic counseling. Background The leukodystrophies are a heterogeneous group of diseases, which primarily affect white matter and for its common presentation as a cerebral palsy-like encephalopathy can lead to misdiagnosis. Hypomyelination disorders constitute the largest single category among leukoencephalopathies of unknown origin. Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a recently defined disorder and only a few patients have been described in the literature. Design/Methods: One adult male patient diagnosed with cerebral palsy at infancy presenting with progressive neurological deterioration was carefully examined and clinical history was reviewed. Imaging, neurophysiologic studies, genetic and metabolic tests were done to describe detailed findings and characteristics. Literature was reviewed regarding similar cases reported with similar clinical findings and tests results. Results: Based on clinical presentation, MRI findings and lack of relevant laboratory tests abnormalities, patient was diagnosed with hypomyelination with atrophy of basal ganglia and cerebellum. Our patient was found to have mild slowed conduction velocities of sensory and motor peripheral nerves. Baclofen and Leucovorin were started as an attempt to improve symptoms and delay further clinical deterioration. Conclusions: Due to the highly variable clinical presentations of the hypomyelination disorders is unlikely that they represent a single disease entity. Cases reported with H-ABC have typical MRI features, are sporadic and clinical laboratory and genetic tests are all unremarkable. Cases reported in the literature were diagnosed on infancy and some of them had improvement of symptoms after symptomatic treatment was started. Disclosure: Dr. De Jesus has nothing to disclose. Dr. Massey has nothing to disclose. Dr. Overby has nothing to disclose.
Neurology International · 2009 · 0 citations · open access
The interplay between the expression and functions of Wnt13 isoforms during apoptosis in bovine aortic endothelial cells
AbstractHypomyelinating leukodystrophies (HLDs) represent a group of congenital rare diseases for which the responsible genes have been identified in recent studies. In this review, we briefly describe the genetic/molecular mechanisms underlying the pathogenesis of HLD and the normal cellular functions of the related genes and proteins. An increasing number of studies have reported genetic mutations that cause protein misfolding, protein dysfunction, and/or mislocalization associated with HLD. Insight into the mechanisms of these pathways can provide new findings for the clinical treatments of HLD.
Cambridge University Press eBooks · 2002 · 0 citations
Leukodystrophies
AbstractThe term leukodystrophy was first introduced by Bielschowsky and Henneberg (1928). In his review of the neuropathology of the leukodystrophies, James Powers et al. (2000) recommended that the term leukodystrophy should be applied only to ‘those progressive diseases of myelin in which a molecular abnormality is responsible for metabolic defects in myelin sheaths or myelin forming cells resulting in confluent destruction, or failed development, of central white matter’. Since the 1990s, remarkable progress has been achieved in the definition of the biochemical defect and the molecular basis of the leukodystrophies (Table 100.1).
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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