DeCure for COG8-congenital disorder of glycosylation
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for COG8-congenital disorder of glycosylation — 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 moduleCOG8-congenital disorder of glycosylation 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 cog8-congenital disorder of glycosylation 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.
What the evidence adds up to
Congenital disorders of glycosylation are a family of about 45 genetic diseases, most affecting protein N-glycosylation, with a frequent neurological component. The conserved oligomeric Golgi (COG) complex has eight subunits; mutations in COG1, COG4, COG7, and COG8 have been linked to human disease. In 2009, a splicing mutation in COG5 (c.1669-15T>C) was identified in a patient with mild psychomotor retardation and delayed motor and language development. Serum glycoproteins showed undersialylation of N- and O-glycans, and retrograde Golgi-to-ER trafficking was markedly delayed in the patient’s fibroblasts; this delay was restored to normal by expressing wild-type COG5 cDNA. The authors concluded that COG deficiency should be considered even in children with mild neurological impairments.
In 2023, a fetus at 24 weeks of pregnancy was found to carry a homozygous COG5 c.95T>G variant, described as the first COG5-CDG patient identified at the fetal stage. Prenatal findings included polyhydramnios, hydrocephaly, abnormal facial features, brain morphology abnormality, spina bifida, vertebral column abnormality, macrocephaly, scoliosis, micrognathia, abnormal kidney morphology, and short femur and humerus lengths. The authors noted that homozygous patients had never been reported before in the literature for COG5-CDG.
A 2022 report described a lethal case of COG6-CDG in a neonate of Albanian origin with skin scaling and erosions, joint contractures, and a homozygous COG6 pathogenic variant previously seen in Greek, Bulgarian, and Turkish individuals, suggesting a possible founder mutation in Southeastern Europe or West Asia. A 2021 review stated that treatment options for CDG remain limited and are often confined to symptomatic management, though some novel therapies aimed at the causative defect or secondary manifestations have moved from bench to bedside.
What is still missing are therapies that directly correct the underlying COG8 defect, any clinical trial data for COG8-CDG specifically, and a clear understanding of how the severity of the disease varies with different mutations. Patient stratification by genotype and residual COG8 function, along with funding for natural history studies and drug screening, would be needed before any treatment could be evaluated.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Annals of the New York Academy of Sciences · 2010 · 220 citations
Congenital disorders of glycosylation
AbstractCongenital (genetic) disorders of glycosylation (CDG) are a rapidly growing disease family, with some 45 members reported since its first clinical description in 1980. Most of these are protein hypoglycosylation diseases, but recently three defects in lipid glycosylation have been identified. Most protein hypoglycosylation diseases are due to defects in the N-glycosylation pathway (16 diseases). The remaining ones affect the O-glycosylation pathway (8 diseases), both the N- and the O-glycosylation pathways, or other pathways (17 diseases). CDG can affect nearly all organs and systems, but there is often an important neurological component. The first-line screening for the N-glycosylation diseases is serum transferrin isoelectrofocusing (IEF), and for the O-glycosylation disorders apo CIII IEF. It has to be stressed that a normal test result does by no means exclude a CDG. In case of an abnormal result and as long as the basic defect has not been elucidated, the disease is labeled CDG-x (CDG-Ix when the transferrin IEF shows a type 1 pattern, and CDG-IIx when it shows a type 2 pattern).
Human Molecular Genetics · 2009 · 113 citations · open access
Deficiency in COG5 causes a moderate form of congenital disorders of glycosylation
AbstractThe conserved oligomeric Golgi (COG) complex is a tethering factor composed of eight subunits that is involved in the retrograde transport of intra-Golgi components. Deficient biosynthesis of COG subunits leads to alterations of protein trafficking along the secretory pathway and thereby to severe diseases in humans. Since the COG complex affects the localization of several Golgi glycosyltransferase enzymes, COG deficiency also leads to defective protein glycosylation, thereby explaining the classification of COG deficiencies as forms of congenital disorders of glycosylation (CDG). To date, mutations in COG1, COG4, COG7 and COG8 genes have been associated with diseases, which range from severe multi-organ disorders to moderate forms of neurological impairment. In the present study, we describe a new type of COG deficiency related to a splicing mutation in the COG5 gene. Sequence analysis in the patient identified a homozygous intronic substitution (c.1669-15T>C) leading to exon skipping and severely reduced expression of the COG5 protein. This defect was associated with a mild psychomotor retardation with delayed motor and language development. Analysis of different serum glycoproteins revealed a CDG phenotype with typical undersialylation of N- and O-glycans. Retrograde Golgi-to-endoplasmic reticulum trafficking was markedly delayed in the patient's fibroblast upon brefeldin-A treatment, which is a hallmark of COG deficiency. This trafficking delay could be restored to normal values by expressing a wild-type COG5 cDNA in the patient cells. This case demonstrates that COG deficiency and thereby CDG must be taken into consideration even in children presenting mild neurological impairments.
Frontiers in Genetics · 2021 · 41 citations · open access
Treatment Options in Congenital Disorders of Glycosylation
AbstractDespite advances in the identification and diagnosis of congenital disorders of glycosylation (CDG), treatment options remain limited and are often constrained to symptomatic management of disease manifestations. However, recent years have seen significant advances in treatment and novel therapies aimed both at the causative defect and secondary disease manifestations have been transferred from bench to bedside. In this review, we aim to give a detailed overview of the available therapies and rising concepts to treat these ultra-rare diseases.
Journal of Inherited Metabolic Disease · 2019 · 31 citations
Keeping an eye on congenital disorders of O‐glycosylation: A systematic literature review
AbstractCongenital disorders of glycosylation (CDG) are a rapidly growing family comprising >100 genetic diseases. Some 25 CDG are pure O-glycosylation defects. Even among this CDG subgroup, phenotypic diversity is broad, ranging from mild to severe poly-organ/system dysfunction. Ophthalmic manifestations are present in 60% of these CDG. The ophthalmic manifestations in N-glycosylation-deficient patients have been described elsewhere. The present review documents the spectrum and incidence of eye disorders in patients with pure O-glycosylation defects with the aim of assisting diagnosis and management and promoting research.
<scp>COG1‐</scp> congenital disorders of glycosylation: Milder presentation and review
AbstractCongenital disorders of glycosylation (CDG) are a heterogeneous group of genetic defects in glycoprotein and glycolipid glycan synthesis and attachment. A CDG subgroup are defects in the conserved oligomeric Golgi complex encoded by eight genes, COG1-COG8. Pathogenic variants in all genes except the COG3 gene have been reported. COG1-CDG has been reported in five patients. We report a male with neonatal seizures, dysmorphism, hepatitis and a type 2 serum transferrin isoelectrofocusing. Exome sequencing identified a homozygous COG1 variant (NM_018714.3: c.2665dup: p.[Arg889Profs*12]), which has been reported previously in one patient. We review the reported patients.
Lethal COG6‐CDG in neonatal patient with arachnodactyly, joint contractures, and skin manifestations: Founder mutation in the Southeastern European population?
AbstractHerein, we report a lethal case of the ultra-rare COG6-congenital disorder of glycosylation (CDG) presenting with skin manifestations (scaling and erosions) and joint contractures in a neonate of Albanian origin. The patient was homozygous for a COG6 pathogenic variant, previously reported in another three individuals of Greek, Bulgarian and Turkish descent. The presence of a founder mutation in the geographical area is possible. The index case emphasizes the need to consider CDGs in neonatal patients with skin manifestations and joint contractures, particularly patients of Southeastern European or West Asian origin.
Molecular Syndromology · 2023 · 4 citations · open access
The First Congenital Disorders of Glycosylation Patient (Fetus) with Homozygous COG5 c.95T>G Variant
AbstractIntroduction: Congenital disorders of glycosylation (CDG) are autosomal recessive hereditary genetic disorders characterized by abnormal glycosylation of N-linked oligosaccharides. Case Presentation: In this research, prenatal testing (24th week of pregnancy) revealed findings like polyhydramnios, hydrocephaly, abnormal facial features/shape, brain morphology abnormality, spina bifida, vertebral column abnormality, macrocephaly, scoliosis, micrognathia, abnormal kidney morphology, short fetal femur length, and short fetal humerus length in the fetus. Whole-exome sequencing was performed; the COG5 gene has shown a pathogenic variant. Discussion: Homozygous patients have never been seen before in the literature for COG5-CDG. We demonstrate the first CDG patient at fetus stage with homozygous COG5 c.95T>G variant.
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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