DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for argininosuccinic aciduria — 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 moduleArgininosuccinic aciduria 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 argininosuccinic aciduria 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
argininosuccinate lyase (ASL) — ASL 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 1K62 · 2.65 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Argininosuccinic aciduria was first described in 1960 as a newly recognised form of mental disease, with the abnormal metabolite identified and preliminary metabolic studies carried out. The condition is a urea cycle defect caused by deficiency of the enzyme argininosuccinate lyase. In a 2017 review of enzyme abnormalities in urea cycle disorders, an ELISA for argininosuccinate lyase protein showed that 8 out of 10 cases of argininosuccinic aciduria had no detectable ASL protein in liver, erythrocytes, cultured skin fibroblasts or cultured amniocytes.
A 1986 report of a patient treated for two years with protein restriction and arginine dietary supplementation described erythrocyte argininosuccinate lyase activity below 2% of normal. The child experienced three episodes of hyperammonaemia (greater than 100 microns) — at birth, at 6.5 months, and at 16 months. Neurological development deteriorated between 14 and 24 months. Hepatomegaly and biochemical hepatitis were accompanied by enlarged mitochondria with tubular paracrystalline inclusions not previously recognised in this disorder.
A 2022 case report described a patient with argininosuccinic aciduria and Silver-Russell syndrome caused by maternal uniparental disomy of chromosome 7, which unmasked a maternally inherited splicing variant in ASL. The phenotype was more severe than a previous case, demonstrating phenotypic variation in this combination. A 2023 report of a Lebanese neonate with severe early manifestation identified a novel homozygous ASL mutation (c.697A>C p.(Thr233Pro)), the first time this variant had been reported.
A 2023 study using ion-exchange chromatography with acidification and heating found that argininosuccinic acid was detectable in all 20 urine samples from individuals with no prior diagnosis of argininosuccinic aciduria, with an average concentration of 27.2 μmol/g Cr and a range of 11.3–47.7 μmol/g Cr. The authors concluded that ASA can be present in the urine of healthy individuals up to 50 μmol/g Cr, contradicting earlier claims that any detectable ASA in urine is diagnostic. What remains missing is systematic newborn screening data using modern LC-MS/MS methods to establish reliable population reference ranges, prospective studies correlating genotype with long-term neurological outcomes, and clinical trials of any pharmacological intervention beyond dietary arginine and protein restriction.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Biochemical Journal · 1960 · 109 citations · open access
Argininosuccinic aciduria: identification and reactions of the abnormal metabolite in a newly described form of mental disease, with some preliminary metabolic studies
Molecular Basis of Enzyme Abnormalities in Urea CycleDisorders
AbstractThis paper deals with enzymological, immunochemical and molecular genetic analyses of citrullinemia and argininosuccinic aciduria. Citrullinemia has been classified by Saheki et al. [J. inher. Metab. Dis. 8: 155-156, 1985] into three types from the properties of the deficient argininosuccinate synthetase (ASS) of the patients. Analysis of hepatic mRNA coding for ASS revealed certain characteristics in type II and III citrullinemic patients whose hepatic ASS protein was low. A newly developed enzyme-linked immunosorbent assay (ELISA) of argininosuccinate lyase (ASL) protein showed that 8 out of ten cases of argininosuccinic aciduria had no detectable ASL protein in the liver, erythrocytes, cultured skin fibroblasts or cultured amniocytes.
Journal of Inherited Metabolic Disease · 1986 · 13 citations
Argininosuccinic aciduria: Long‐term treatment with arginine
AbstractThe presentation and 2 year treatment of a patient with argininosuccinic aciduria is reported. Erythrocyte argininosuccinate lyase activity was less than 2% of normal. Long-term management included protein restriction and arginine dietary supplementation. The child experienced three episodes of hyperammonaemia (greater than 100 microns), the first at birth, the second at 6.5 months and the third at 16 months. Neurological development deteriorated between 14 and 24 months. Hepatomegaly and biochemical hepatitis, a feature of this condition, was accompanied by enlarged mitochondria with tubular paracrystalline inclusions not previously recognized in this disorder.
Human Genome Variation · 2022 · 3 citations · open access
Maternal uniparental disomy of chromosome 7 underlying argininosuccinic aciduria and Silver-Russell syndrome
AbstractWe describe a patient presenting with argininosuccinic aciduria and Silver-Russell syndrome (SRS). SRS was caused by maternal uniparental disomy of chromosome 7 (UPD(7)mat). UPD(7)mat also unmasked a maternally inherited splicing variant in ASL on chromosome 7, leading to the onset of argininosuccinic aciduria. The phenotype of the present case was more severe than that of a previous case, demonstrating a phenotypic variation in the combination of argininosuccinic aciduria and SRS.
Clinical Chemistry · 2023 · 1 citations · open access
A-326 Argininosuccinic Acid - is it Routinely Detectable in the Urine of Healthy Individuals?
AbstractAbstract Background Argininosuccinic aciduria is a genetic disorder that results in elevated levels of argininosuccinic acid (ASA) in urine and blood. While there is seemingly a consensus within the clinical literature that any detectable amount of ASA in blood/plasma is diagnostic for argininosuccinic aciduria, yet there is conflict as to whether ASA in urine can be found in unaffected individuals. Some literature states that ASA should not be found in the urine of a healthy individual, while other literature reports low levels of ASA in the urine of healthy individuals. Additionally, many laboratories do not have a normal range for ASA within urine, which implies that any level of ASA found within urine is indicative of argininosuccinic aciduria. This conflict may in part be due to differences in the methods used to determine ASA levels. Newer liquid chromatography tandem mass spectrometry (LCMSMS) methods have been shown to be more sensitive than ion-exchange chromatography (IEC) based amino acid methods for detection of ASA. Additionally, the detection of ASA via IEC requires the heating and acidification of the sample to convert ASA into a single peak for quantitation. Heating and acidification is not routinely done for urine amino acid analysis with IEC; with routine IEC urine amino acid analysis, ASA migrates as three small peaks that may go unnoticed. In our clinical laboratory, which utilizes the less sensitive IEC method, our procedure describes the presence of any ASA in urine as diagnostic for argininosuccinic aciduria. Given the conflicting literature, we set forth to determine whether low levels can be detected in unaffected individuals with an IEC method, and if so, establish a normal range of ASA levels in urine with IEC. Methods Twenty waste urine samples from patients with no prior diagnoses of argininosuccinic aciduria were evaluated. ASA levels within the samples were determined via high performance ion exchange chromatography for separation of compounds followed by derivatization with ninhydrin for spectrophotometric detection with a Hitachi Amino Acid analyzer. The samples were acidified and heated, which converts ASA into a single anhydride peak for accurate quantitation, and the results were normalized to urine creatinine. Results ASA was detected in all twenty urine samples, with an average ASA concentration of 27.2 μmol/g Cr and a range of 11.3–47.7 μmol/g Cr. Conclusion Given these findings, our clinical laboratory procedure has been updated to include the information that ASA can be present in the urine of healthy individuals up to a concentration of 50 μmol/g Cr. Other clinical laboratories that analyze urine to identify argininosuccinic aciduria should be aware of the misinformation in the literature that claims that ASA is not present in the urine of healthy individuals.
SVOA Paediatrics · 2023 · 0 citations · open access
A Novel Variant of ASL Gene Mutation in a Lebanese Neonate with Severe Argininosuccinic Aciduria Phenotype
AbstractArgininosuccinic aciduria is a urea cycle defect associated with deficiency in argininosuccinate lyase enzyme, leading to a severe hyperammonemic encephalopathy, epilepsy and hepatopathy. Only very few known mutations have been linked with a severe phenotype. Here we report the case of a Lebanese newborn child with a very early manifestation of argininosuccinic aciduria, his genetic studies confirmed the presence of a mutation in the ASL gene (c.697A>C p. (Thr233Pro) at the homozygous state. To our knowledge, this is the first time this variant has been reported in literature.
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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