DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Congenital bile acid synthesis defect — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCongenital bile acid synthesis defect maps to a 2-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 congenital bile acid synthesis defect 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
aldo-keto reductase family 1 member D1 (AKR1D1) — AKR1D1 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 napdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3BUV · 1.35 Å · ligand NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (NAP). Experimental structure, not a prediction.
What the evidence adds up to
In 1988, a new inborn error in bile acid synthesis was described in identical twin infants with severe intrahepatic cholestasis. The defect involved the enzyme delta 4-3-oxosteroid 5 beta-reductase, which normally converts the intermediates 7 alpha-hydroxy-4-cholesten-3-one and 7 alpha,12 alpha-dihydroxy-4-cholesten-3-one into the 3 alpha-hydroxy-5 beta (H) products needed for chenodeoxycholic and cholic acid synthesis. The twins excreted taurine conjugated unsaturated hydroxy-oxo-bile acids as 75–92% of total bile acids. Fasting serum bile acid concentrations were greater than 37 mumol/litre; chenodeoxycholic acid was the major bile acid, but significant amounts of allo(5 alpha-H)-bile acids (approximately 30%) were present. Biliary bile acid concentration was less than 2 mumol/litre and consisted of chenodeoxycholic, allo-chenodeoxycholic, and allo-cholic acids.
By 2006, six of the seven known genetic defects in bile acid synthesis had been characterised using mass spectrometry screening of urine and molecular identification of mutations. Oral cholic acid therapy was reported as effective in most of these defects, making early diagnosis crucial for optimum clinical prognosis. A 2018 review confirmed that oral cholic acid is a safe and effective therapy for the most common defects, which if untreated may lead to early cirrhosis and liver failure. The review noted that the diagnosis is suggested by absence of itching, normal gamma-glutamyl transferase, and normal serum bile acids, and is confirmed by urinary mass spectrometry and gene analysis.
What remains missing is large-scale, long-term outcome data for cholic acid treatment across all identified defects, given the rarity of these disorders. No randomised controlled trials have been reported. Patient stratification by specific genetic mutation and by age at treatment initiation is not yet established, and the cost and availability of cholic acid therapy and mass spectrometry screening limit widespread implementation.
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 Clinical Investigation · 1988 · 255 citations · open access
Delta 4-3-oxosteroid 5 beta-reductase deficiency described in identical twins with neonatal hepatitis. A new inborn error in bile acid synthesis.
AbstractA new inborn error in bile acid synthesis, manifest in identical infant twins as severe intrahepatic cholestasis, is described involving the delta 4-3-oxosteroid 5 beta-reductase catalyzed conversion of the key intermediates, 7 alpha-hydroxy-4-cholesten-3-one and 7 alpha,12 alpha-dihydroxy-4-cholesten-3-one for chenodeoxycholic and cholic acid synthesis, to the respective 3 alpha-hydroxy-5 beta (H) products. This defect was detected by fast atom bombardment ionization-mass spectrometry from an elevated excretion and predominance of taurine conjugated unsaturated hydroxy-oxo-bile acids. Gas chromatography-mass spectrometry confirmed these to be 7 alpha-hydroxy-3-oxo-4-cholenoic and 7 alpha,12 alpha-dihydroxy-3-oxo-4-cholenoic acids (75-92% of total). Fasting serum bile acid concentrations were greater than 37 mumol/liter; chenodeoxycholic acid was the major bile acid, but significant amounts of allo(5 alpha-H)-bile acids (approximately 30%) were present. Biliary bile acid concentration was less than 2 mumol/liter and consisted of chenodeoxycholic, allo-chenodeoxycholic, and allo-cholic acids. These biochemical findings, which were identical in both infants, indicate a defect in bile acid synthesis involving the conversion of the delta 4-3-oxo-C27 intermediates into the corresponding 3 alpha-hydroxy-5 beta(H)-structures, a reaction that is catalyzed by a delta 4-3-oxosteroid-5 beta reductase enzyme. This defect resulted in markedly reduced primary bile acid synthesis and concomitant accumulation of delta 4-3-oxo-and allo-bile acids. These findings indicate a pathway in bile acid synthesis whereby side chain oxidation can occur despite incomplete alterations to the steroid nucleus, and lend support for an active delta 4-3-oxosteroid 5 alpha-reductase catalyzing the conversion of the delta 4-3-oxosteroid intermediates to the respective 3 alpha-hydroxy-5 alpha(H)-structures.
Journal of Pediatric Gastroenterology and Nutrition · 2006 · 138 citations
Defects in Bile Acid Biosynthesis‐Diagnosis and Treatment
AbstractBile acid synthetic defects represent a specific category of metabolic liver disease. This article highlights the history and summarizes our analytical approach to the diagnosis and treatment of genetic defects in bile acid synthesis. By the application of mass spectrometry as a screening tool, it is possible to perform rapid diagnosis of potential inborn errors in bile acid synthesis from urinary bile acid analysis. Molecular techniques then afford the identification of specific mutations in genes encoding the enzymes responsible for bile acid synthesis. Using this approach, 6 of the 7 known genetic defects that are causes of progressive cholestatic liver disease, syndromes of fat-soluble vitamin malabsorption, or neurological disease, have been characterized. Bile-acid therapy using oral cholic acid has proven effective in most of these bile acid synthetic defects making early diagnosis crucial to optimum clinical prognosis.
Institutional Research Information System University of Ferrara (University of Ferrara) · 2018 · 0 citations
L’acido colico nel trattamento degli errori congeniti del metabolismo degli acidi biliari
AbstractInborn errors of primary bile acid synthesis are rare genetic disorders that cause chronic liver disease, steatorrhea and fat-soluble vitamins deficiency in childhood. Absence of itching, normal γGT and serum bile acids suggest the diagnosis, confirmed by urinary mass spectrometry and gene analysis. Oral cholic acid is a safe and effective therapy for the most common defects that if untreated may lead to early cirrhosis and \nliver failure.
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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