DeCure for STT3A-congenital disorder of glycosylation
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for STT3A-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 moduleSTT3A-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 stt3a-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
Mutations in STT3A cause a congenital disorder of glycosylation (CDG) characterised by neurologic abnormalities, hypotonia, intellectual disability, failure to thrive and feeding problems. The 2013 report describes two unrelated consanguineous families, each with a different homozygous mutation: a c.1877T>C change in STT3A producing a p.Val626Ala substitution, and a c.1539+20G>T intronic mutation in STT3B. Both mutations impaired glycosylation of a GFP biomarker and were rescued by the corresponding cDNA. In fibroblasts carrying the mutated gene, glycosylation of STT3A- and STT3B-specific acceptors was decreased. Expression of the STT3A p.Val626Ala allele in STT3A-deficient HeLa cells did not rescue glycosylation. The STT3A mutation significantly impaired glycosylation of the biomarker transferrin, whereas the STT3B mutation only slightly affected it. No additional cases were found in the authors’ collection or in database searches. The authors note that additional cases of STT3B-CDG may be missed by transferrin analysis and will require exome or genome sequencing.
A 2019 systematic review of pure O-glycosylation defects found ophthalmic manifestations in 60% of patients, but this review explicitly excludes N-glycosylation-deficient patients such as those with STT3A-CDG. A 2013 review of CDG and intellectual disability states that two thirds of known CDGs are associated with intellectual disabilities and that most affected individuals need support services throughout their lives. That review also notes that the initial clinical presentation varies significantly among individuals, even between affected siblings.
A 2024 overview of CDG treatment states that available treatment options are still quite limited and that mostly we are only able to manage symptoms rather than address the underlying cause. It notes that recent years have brought advances for some CDG, with therapies targeting root cause and manifestations moving from research to practical application, but does not name any specific drug or therapy for STT3A-CDG. A 2022 case report of SRD5A3-CDG, a different CDG, describes a seven-year-old boy with developmental delay, intellectual disability, ophthalmological abnormalities, cerebellar abnormalities, ataxia, hypotonia, and telangiectasia, but this is not relevant to STT3A-CDG.
What is still missing for STT3A-CDG is any published treatment trial, any drug repurposing data, any patient stratification strategy, and any funding directed specifically at this ultra-rare disorder. The only molecular intervention reported is cDNA rescue in cell lines, which is not a clinical therapy.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Human Molecular Genetics · 2013 · 86 citations · open access
Mutations in STT3A and STT3B cause two congenital disorders of glycosylation
AbstractWe describe two unreported types of congenital disorders of glycosylation (CDG) which are caused by mutations in different isoforms of the catalytic subunit of the oligosaccharyltransferase (OST). Each isoform is encoded by a different gene (STT3A or STT3B), resides in a different OST complex and has distinct donor and acceptor substrate specificities with partially overlapping functions in N-glycosylation. The two cases from unrelated consanguineous families both show neurologic abnormalities, hypotonia, intellectual disability, failure to thrive and feeding problems. A homozygous mutation (c.1877T > C) in STT3A causes a p.Val626Ala change and a homozygous intronic mutation (c.1539 + 20G > T) in STT3B causes the other disorder. Both mutations impair glycosylation of a GFP biomarker and are rescued with the corresponding cDNA. Glycosylation of STT3A- and STT3B-specific acceptors is decreased in fibroblasts carrying the corresponding mutated gene and expression of the STT3A (p.Val626Ala) allele in STT3A-deficient HeLa cells does not rescue glycosylation. No additional cases were found in our collection or in reviewing various databases. The STT3A mutation significantly impairs glycosylation of the biomarker transferrin, but the STT3B mutation only slightly affects its glycosylation. Additional cases of STT3B-CDG may be missed by transferrin analysis and will require exome or genome sequencing.
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.
Developmental Disabilities Research Reviews · 2013 · 28 citations
Congenital disorders of glycosylation and intellectual disability
AbstractThe congenital disorders of glycosylation (CDG) are a rapidly growing group of inborn errors of metabolism that result from defects in the synthesis of glycans. Glycosylation is a major post-translational protein modification and an estimated 2% of the human genome encodes proteins for glycosylation. The molecular bases for the current 60 disorders, affecting approximately 800 individuals, have been identified, many in the last 5 years. CDG should be considered in any multi-system syndrome or single tissue disorder not explained by the identification of another disorder. The initial clinical presentation varies significantly among individuals, even between affected siblings. However, two thirds of the known CDGs are associated with intellectual disabilities and most affected individuals need support services throughout their lives. Additional disorders of glycosylation are likely to be characterized over time.
Molecular Genetics and Metabolism · 2024 · 12 citations · open access
Treatment of congenital disorders of glycosylation: An overview
AbstractWhile the identification and diagnosis of congenital disorders of glycosylation (CDG) have rapidly progressed, the available treatment options are still quite limited. Mostly, we are only able to manage the disease symptoms rather than to address the underlying cause. However, recent years have brought about remarkable advances in treatment approaches for some CDG. Innovative therapies, targeting both the root cause and resulting manifestations, have transitioned from the research stage to practical application. The present paper aims to provide a detailed overview of these exciting developments and the rising concepts that are used to treat these ultra-rare diseases.
Clinical Case Reports · 2022 · 3 citations · open access
A rare case of <scp>SRD5A3‐CDG</scp> in a patient with ataxia and telangiectasia: A case report
AbstractSteroid 5α-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is an extremely rare congenital disease. Common manifestations are developmental delay, intellectual disability, ophthalmological abnormalities, cerebellar abnormalities, ataxia, and hypotonia. Here, we discuss a seven-year-old boy with SRD5A3-CDG (homozygous variant c.57G>A [p.Trp19Ter]), featuring the unprecedented finding of telangiectasia.
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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