DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for mucolipidosis type II — 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 moduleMucolipidosis type II 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 mucolipidosis type ii 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
N-acetylglucosamine-1-phosphate transferase subunits alpha and beta (GNPTAB) — GNPTAB 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 ud1drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9BGF · 2.9 Å · ligand URIDINE-DIPHOSPHATE-N-ACETYLGLUCOSAMINE (UD1). Experimental structure, not a prediction.
What the evidence adds up to
Mucolipidosis type II (I-cell disease) and type III are caused by mutations in the GNPTA gene, which codes for the alpha/beta subunits of GlcNAc-phosphotransferase. In five Korean patients, seven mutations were identified in GNPTA, all nonsense or frameshift in type II patients, while a splicing site mutation combined with a nonsense or frameshift mutation was found in two type IIIA patients. No mutations were found in the GNPTAG gene, which codes for the gamma subunits. Complementation analysis in fibroblasts showed that mucolipidosis II is genetically identical to one of three mucolipidosis III complementation groups (ML IIIA), and that GlcNAc-phosphotransferase is a multicomponent enzyme. The same analysis found that genetic heterogeneity exists within these disorders, with intragenic complementation possible.
Clinical variability is substantial. Nine patients with mucolipidosis II showed remarkable differences in age of onset, organ involvement, and radiological findings, including pericardial effusion and profound brain atrophy, and striking differences were seen even between two affected siblings. In five patients with mucolipidosis IV (a different disorder), none progressed beyond a developmental age of 15 months, one died of aspiration at 17 years, and the oldest reached puberty at 20 years and developed coarse face at 30 years. A single African American patient with mucolipidosis IV had intracytoplasmic inclusions in corneal endothelium, a finding not previously reported; the disorder is predominantly found in individuals of Jewish descent.
Humoral immune function may differ between subtypes. In three Brazilian patients with mucolipidosis III gamma, the residual GlcNAc-1-phosphotransferase activity appeared sufficient to maintain B-cell function and lysosomal enzyme targeting, unlike the impaired immune system seen in ML II patients. No data on infection rates or antibody responses were provided for these three patients.
What is still missing is any clinical trial of a drug for mucolipidosis type II. No therapy has been tested in patients. The genetic and clinical heterogeneity means that any future trial would need to stratify by mutation type and residual enzyme activity, and would require long-term follow-up to capture the variable natural history. Funding for such trials remains absent.
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 Mutation · 2005 · 80 citations
Identification of mutations in the GNPTA (MGC4170) gene coding for GlcNAc-phosphotransferase α/β subunits in Korean patients with mucolipidosis type II or type IIIA
AbstractMucolipidosis types II and III are autosomal recessive inherited diseases caused by a deficiency in the lysosomal enzyme N-acetylglucosamine-1 phosphotransferase (GlcNAc-phosphotransferase), which adds phosphate to function as a recognition marker for the uptake and transport of lysosomal enzymes. We investigated mutations in the GNPTA (MGC4170) gene, which codes for the alpha/beta subunits of phosphotransferase, and in the GNPTAG gene, which codes for its gamma subunits in five Korean patients with mucolipidosis type II or IIIA. We identified seven mutations in the GNPTA gene, but none in GNPTAG. The mutations in type II patients included p.Q104X (c.310C>T), p.R1189X (c.3565C>T), p.S1058X (c.3173C>G), p.W894X (c.2681G>A), and p.H1158fsX15 (c.3474_3475delTA), all of which are nonsense or frameshift mutations. However, a splicing site mutation, IVS13+1G>A (c.2715+1G>A) was detected along with a nonsense or a frameshift mutation (p.R1189X or p.E858fsX3 (c.2574_2575delGA)) in two mucolipidosis type IIIA patients. This report shows that mutations in the GNPTA gene coding for the alpha/beta subunits of phosphotransferase, and not mutations in the GNPTAG gene, account for most of the genetic mutations found in Korean patients with mucolipidosis type II or IIIA.
American Journal of Medical Genetics · 1991 · 69 citations
Mucolipidosis type IV: Clinical manifestations and natural history
AbstractThe clinical manifestations and psychomotor development of five patients with mucolipidosis IV (MLIV) from three Ashkenazi-Jewish families are reported. The presenting symptoms were hypotonia, developmental delay, corneal clouding, and puffy eyelids. Four of the patients had convergent strabismus and none progressed beyond a developmental age of 15 months. One patient died of aspiration at 17 years while the oldest patient entered puberty at 20 years, developed a coarse face at 30 years, and is now 32 years old. Histopathological studies in four patients showed storage changes characteristic of MLIV.
Journal of Inherited Metabolic Disease · 2003 · 56 citations · open access
The osteodystrophy of mucolipidosis type III and the effects of intravenous pamidronate treatment
AbstractMucolipidosis type III (ML III; McKusick 252600) is a rare lysosomal storage disease in which skeletal involvement is prominent, in particular the destruction of vertebral bodies and the femoral heads. We describe studies in two siblings with ML III that suggest the presence of a distinct metabolic bone disorder. Biochemical indices of bone turnover were increased, and transiliac bone biopsy demonstrated both trabecular osteopenia and marked subperiosteal bone resorption. Intravenous pamidronate treatment given monthly for a year was well tolerated and produced dramatic clinical effects, with reduction in bone pain and improvements in mobility, despite incomplete suppression of bone resorption as assessed by biochemical, radiographic and histological criteria. Bisphosphonate therapy may have an important role in the management of bone pain in ML III, as it does in the related lysosomal disorder of Gaucher disease.
Journal of Clinical Investigation · 1983 · 47 citations · open access
Mucolipidosis II and III. The genetic relationships between two disorders of lysosomal enzyme biosynthesis.
AbstractThe genetic relationships between the multiple variants of mucolipidosis II (I-cell disease) and mucolipidosis III (pseudo-Hurler polydystrophy) were investigated with a sensitive genetic complementation analysis procedure. These clinically distinct disorders have defects in the synthesis of a recognition marker necessary for the intracellular transport of acid hydrolases into lysosomes. Both disorders are associated with an inherited deficiency of a uridine diphosphate-N-acetyl-glucosamine: lysosomal enzyme precursor N-acetyl-glucosamine-phosphate transferase activity. We had previously shown that both disorders are genetically heterogeneous. Complementation analysis between mucolipidosis II and III fibroblasts indicated an identity of mucolipidosis II with one of the three mucolipidosis III complementation groups (ML IIIA), suggesting a close genetic relationship between these groups. The presence of several instances of complementation within this group suggested an intragenic complementation mechanism. Genetic complementation in heterokaryons resulted in increases in N-acetyl-glucosamine-phosphate transferase activity, as well as in the correction of lysosomal enzyme transport. This resulted in increases in the intracellular levels of several lysosomal enzymes and in the correction of the abnormal electrophoretic mobility pattern of intracellular beta-hexosaminidase. The findings demonstrate that a high degree of genetic heterogeneity exists within these disorders. N-acetyl-glucosamine-phosphate transferase is apparently a multicomponent enzyme with a key role in the biosynthesis and targeting of lysosomal enzymes.
Inter‐ and intrafamilial variability in mucolipidosis II (I‐cell disease)
AbstractIn this paper nine patients with mucolipidosis II (I-cell disease) are described. They had clinical features commonly found in mucolipidosis II, including disproportionate dwarfism, coarse facial features and mental retardation. However, there was remarkable variability in age of onset, organ manifestation and radiological findings. Some had unusual clinical symptoms including pericardial effusion and profound brain atrophy. Striking differences in phenotypic expression were also seen in two affected siblings. Clinical heterogeneity is observed not only in mucolipidosis II but also in many other lysosomal storage disorders. The factors that may contribute to this clinical diversity are discussed.
Mucolipidosis IV in an African American Patient with New Findings on Electron Microscopy
AbstractPURPOSE: We report an unusual case of mucolipidosis IV in a patient of African ancestry, with intracytoplasmic inclusions of the corneal endothelium found on electron microscopy. METHOD: Clinical description with light and electron microscopy. RESULTS: We describe a case of mucolipidosis IV diagnosed in a patient of African ancestry after penetrating keratoplasty. Electron microscopic evaluation revealed intracytoplasmic inclusions in both the corneal epithelium and endothelium. CONCLUSION: The diagnosis of mucolipidosis in a patient of African ancestry is unusual, as this genetic disorder is found predominantly in individuals of Jewish descent. Corneal endothelial involvement in mucolipidosis IV has not previously been reported.
Genetics and Molecular Biology · 2019 · 0 citations · open access
Humoral immune response in adult Brazilian patients with Mucolipidosis III gamma
AbstractMucolipidosis II and III (ML II and III) alpha/beta and ML III gamma are lysosomal diseases caused by GlcNAc-1-phosphotransferase deficiency. Previous data indicate that MLII patients have functionally impaired immune system that contributes to predisposition to infections.We evaluated the immunological phenotype of three Brazilian patients with ML III gamma. Our data suggest that the residual activity of GlcNAc-1-phosphotransferase in patients with ML III gamma is enough to allow the targeting of the lysosomal enzymes required for B-cell functions maintenance.
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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