DeCure for Alpha-N-acetylgalactosaminidase deficiency type 3
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for alpha-N-acetylgalactosaminidase deficiency type 3 — 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 moduleAlpha-N-acetylgalactosaminidase deficiency type 3 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 alpha-n-acetylgalactosaminidase deficiency type 3 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
alpha-N-acetylgalactosaminidase (NAGA) — NAGA 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 3s,4r,5s,6rdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4DO4 · 1.4 Å · ligand N-[(3S,4R,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)piperidin-3-yl]acetamide (DJN). Experimental structure, not a prediction.
What the evidence adds up to
alpha-N-acetylgalactosaminidase deficiency (Schindler disease) is a lysosomal disorder with distinct infantile and adult forms. As of 2006, only 12 patients from eight families had been described. A Spanish infant presented with hepatomegaly and cardiomyopathy, features not previously reported in the disease. There was no dysmorphism or neurological involvement. The patient died at eight months of age. Enzyme activity in fibroblasts was 1.6% of controls and in liver 0.57% of controls. Other lysosomal enzyme activities linked to infantile cardiomyopathy were normal. The patient was a compound heterozygote for a novel mutation p.D217N (c.649G>A) in exon 6 and the previously reported mutation p.E325K (c.973G>A) in exon 8. This case broadens the clinical spectrum and suggests Schindler disease should be considered in metabolic cardiomyopathies.
In a 1977 study of mutagen-treated human lymphoblastoid clones, two clones were found deficient in lysosomal acid hydrolases. One clone, N32, was deficient in N-acetyl hexosaminidase A and B, resembling Sandhoff variant of Tay-Sachs disease. The other clone, G3, was deficient in alpha-galactosidase A, resembling Fabry's disease. No storage of natural substrates could be demonstrated in these clones. Karyotype analysis showed no chromosome rearrangement or loss, suggesting single point mutations might account for the enzyme loss.
A 2022 study measured plasma α-N-acetylgalactosaminidase concentrations in 32 patients with bipolar affective disorder and 32 healthy controls. Mean α-NAGAL values were significantly lower in patients than controls. A strong negative correlation was found between α-NAGAL levels and Young Mania Rating Scale scores, and a positive correlation between age of disease onset and α-NAGAL levels. The authors propose that low α-NAGAL concentrations may cause accumulation of glycoproteins in brain lysosomes during gestation, contributing to bipolar disorder symptoms, but note deficiency may not be the sole cause.
No drug treatment for alpha-N-acetylgalactosaminidase deficiency type 3 is mentioned in any of these abstracts. What remains missing is any clinical trial of enzyme replacement, gene therapy, or substrate reduction therapy for this ultra-rare disorder, as well as systematic patient registries, natural history data, and validated biomarkers to stratify patients by disease severity or progression.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Inherited Metabolic Disease · 2006 · 20 citations
A new infantile case of α‐<i>N</i>‐acetylgalactosaminidase deficiency. Cardiomyopathy as a presenting symptom
Abstractalpha-N-Acetylgalactosaminidase deficiency is a lysosomal disorder with clinically very different infantile and adult forms. To date, 12 patients from eight families are known. Neuroaxonal dystrophy or moderate psychomotor retardation, without visceral involvement, have been reported in the infantile form. We describe a new Spanish patient with Schindler disease who presented with hepatomegaly and cardiomyopathy, traits not previously associated with this disease. There was no dysmorphism or neurological involvement in the patient, who died at the age of 8 months. alpha-N-Acetylgalactosaminidase activity was reduced in fibroblasts and liver to 1.6% and 0.57% of controls, respectively. Several lysosomal enzyme activities associated with infantile cardiomyopathy were found in the normal ranges. The patient was a compound heterozygote for the novel mutation p.D217N (c.649G>A) in exon 6 and the already reported mutation p.E325K (c.973G>A) in exon 8. The description of this new case broadens the clinical spectrum of the infantile forms and indicates that Schindler disease should be considered in the diagnosis of metabolic cardiomyopathies.
The deficiency of a lysosomal acid hydrolase in two clones derived from the human lymphoblastoid line F137 after mutagen treatment
AbstractTwo clones (out of a total of 181 clones tested) derived from the human lymphoblastoid (lymphoid) line F137 after mutagen treatment were found to be deficient in a lysosomal acid hydrolase. The clone N32 derived from EMS-treated F137 is deficient in N-acetyl hexosaminidase A and B but contains normal levels of N-acetyl hexosaminidase C and low levels of an enzyme resembling N-acetyl hexosaminidase S. Thus the enzyme deficiency in this clone appears to resemble the so-called Sandhoff variant of Tay-Sachs disease, a disease inherited as an autosomal recessive condition. The clone G3 derived from MNNG treated F137 is deficient in alpha-galactosidase A. This clone resembles the situation in X-linked Fabry's disease. Karyotype analysis of the clones failed to reveal any chromosome rearrangement or losses of chromosomal material that might have accounted for the mutations and it is suggested that a single point mutation might in each case account for the loss of enzyme activity. No storage of the natural substrates of the two enzymes could be demonstrated in the clones.
The World Journal of Biological Psychiatry · 2022 · 3 citations
Low α-N-acetylgalactosaminidase plasma concentration correlates with the presence and severity of the bipolar affective disorder
AbstractOBJECTIVES: Believing that a neurodevelopmental pathology may cause bipolar affective disorder (BAD), we aimed to measure the concentrations of α-N-acetylgalactosaminidase (α-NAGAL), a lysosomal enzyme. METHODS: The study included 32 patients with BAD and 32 healthy controls. The Young Mania Rating Scale was used to measure the severity of the disease. Serum α-N-acetylgalactosaminidase concentrations were measured in all blood samples using the human α-N-acetylgalactosaminidase ELISA Kit. RESULTS: A statistically significant difference was found in the α-NAGAL values between the groups. The mean α-NAGAL values of BAD patients are lower than the mean α-NAGAL values of the control group. A strong negative and statistically significant relationship was found between the α-NAGAL values of patients with BAD and their Young Mania Rating Scale scores. And a positive strong correlation was found between the age of onset of the disease and α-NAGAL levels. CONCLUSIONS: Low α-N-acetylgalactosaminidase concentrations may cause the accumulation of some glycoproteins in the lysosomes in the brain during the gestational period, producing the clinical symptoms of BAD. α-N-acetylgalactosaminidase deficiency may not be the only cause of BAD, but it may be an important factor in the aetiology of this disease.
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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