DeCure for Congenital bile acid synthesis defect 5
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for congenital bile acid synthesis defect 5 — 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 moduleCongenital bile acid synthesis defect 5 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 congenital bile acid synthesis defect 5 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
ATP binding cassette subfamily D member 3 (ABCD3) — ABCD3 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 atpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9W65 · 2.94 Å · ligand ADENOSINE-5'-TRIPHOSPHATE (ATP). Experimental structure, not a prediction.
What the evidence adds up to
Congenital bile acid synthesis defect 5 is one of several rare genetic disorders that together account for about 2% of persistent cholestasis in infants. The 2002 review describes these defects as potentially life-threatening and notes that the associated liver disease can range from mild to severe, with progression most rapid when toxic monohydroxy and unsaturated oxo-bile acids accumulate. Pathological findings include intralobular cholestasis with giant cell transformation, necrotic hepatocytes, and fibrosis at the portal limiting plate. The review states that replacement of deficient primary bile acids can produce beneficial feedback inhibition and enhance bile flow, but it does not report specific survival or response rates.
A 2024 systematic review assessed cholic acid treatment across 162 patients with various bile acid synthesis defects, including 62 with 3β-hydroxy-Δ5-C27-steroid oxidoreductase deficiency and 13 with Δ4-3-oxosteroid 5β-reductase deficiency. Treatment duration ranged from one week to 16.5 years. The review found that the available data came entirely from case reports and case series, with an overall risk of bias rated as critical in one study, serious in four, and moderate in nine. Major problems included missing data in ten studies and generalised data in eight. The authors concluded that the evidence is insufficient to draw definite conclusions on the effectiveness or safety of cholic acid in these patients.
A 2025 case series of three first-degree relatives with congenital bile acid synthesis defect type 2 (AKR1D1 deficiency) reported that all patients showed significant clinical improvement after starting cholic acid. A 2018 review in Italian describes oral cholic acid as a safe and effective therapy for the most common defects, warning that untreated disease may lead to early cirrhosis and liver failure. However, the 1983 review notes that the relationship between abnormal bile acid production and disease pathogenesis remains unknown, and that more studies are needed.
What is still missing are controlled trials with adequate sample sizes, standardised outcome measures, and long-term follow-up. The 2024 systematic review specifically calls for an independent international disease registry to better use existing real-world data, since missing data and lack of wash-out periods between treatments have undermined the current evidence base. No study has yet stratified patients by genetic subtype or disease severity in a way that allows reliable prediction of who will benefit from cholic acid 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.
Pediatric and Developmental Pathology · 2002 · 156 citations
Bile Acid Synthetic Defects and Liver Disease: A Comprehensive Review
AbstractBile acid synthetic defects (BASD), uncommon genetic disorders that are responsible for approximately 2% of persistent cholestasis in infants, are reviewed with emphasis on morphology of associated liver disease. The associated liver diseases may be life threatening, and are treatable, usually by replacement of deficient primary bile acids. Specific diagnosis is made by analysis of body fluids (bile, blood, and urine) using fast atom bombardment-mass spectroscopy (FAB-MS) and gas chromatography-mass spectroscopy (GC-MS). Inborn errors have been demonstrated for four single enzymes involved in modification of the sterol nucleus and in five steps in modification of the side-chain to form cholic and chenodeoxycholic acids, the primary bile acids. With few exceptions, BASD cause liver diseases that vary from severe to mild depending on the defect. In three of four known defects of sterol nucleus modification, liver disease is progressive. Progression of liver disease is most rapid when the defect results in accumulation of toxic monohydroxy and unsaturated oxo-bile acids. Liver disease may be transient, delayed in onset and mild. Reduced bile flow caused by atypical bile acids contributes to cholestasis and may be the dominant factor in defects of side-chain synthesis, peroxisomal abiogenesis and S-L-O syndrome. Pathological findings may include intralobular cholestasis with giant cell transformation, prevalence of necrotic hepatocytes including giant cell forms, and hepatitic injury confined to the portal limiting plate where the smallest bile ductules may be injured and where fibrosis typically develops. Interlobular bile ducts are usually spared. Ultrastructure of liver reveals nonspecific changes with the possible exception of unusual canalicular morphology in some defects. The course of BASD may be modified by replacement of deficient primary bile acids, which produces beneficial feedback inhibition of abnormal bile acid production and enhances choluresis. Giant cell transformation is present in all symptomatic infants with BASD and seems to have a more consistent association with BASD than with the many other liver diseases in infants where it occurs. We hypothesize that immature hepatocytes of infants may fuse to form multinucleate hepatocytes whenever atypical or toxic bile acids are present and the pool of normal bile acids is critically reduced.
Current Opinion in Gastroenterology · 2017 · 33 citations · open access
Bile acid disease
AbstractPURPOSE OF REVIEW: Our objective was to review advances in bile acids in health and disease published in the last 2 years. Bile acid diarrhea (BAD) is recognized as a common cause of chronic diarrhea, and its recognition has been facilitated by development of new screening tests. RECENT FINDINGS: Primary BAD can account for 30% of cases of chronic diarrhea. The mechanisms leading to BAD include inadequate feedback regulation by fibroblast growth factor 19 (FGF-19) from ileal enterocytes, abnormalities in synthesis or degradation of proteins involved in FGF-19 regulation in hepatocytes and variations as a function of the bile acid receptor, TGR5 (GPBAR1). SeHCAT is the most widely used test for diagnosis of BAD. There has been significant validation of fasting serum FGF-19 and 7 α-hydroxy-cholesten-3-one (C4), a surrogate measure of bile acid synthesis. Bile acid sequestrants are the primary treatments for BAD; the farnesoid X-receptor-FGF-19 pathway provides alternative therapeutic targets for BAD. Bile acid-stimulated intestinal mechanisms contribute to the beneficial effects of bariatric surgery on obesity, glycemic control and the treatment of recurrent Clostridium difficile infection. SUMMARY: Renewed interest in the role of bile acids is leading to novel management of diverse diseases besides BAD.
Orphanet Journal of Rare Diseases · 2024 · 3 citations · open access
The clinical and biochemical effectiveness and safety of cholic acid treatment for bile acid synthesis defects: a systematic review
AbstractAbstract Background Bile acid synthesis defects (BASDs) can be severely disabling involving the liver and nervous system, potentially due to elevated levels of toxic C 27 -bile acid intermediates. Cholic acid (CA) supplementation is hypothesized to decrease bile acid production, stimulate bile secretion and -flow, and slowing down disease progression. This systematic review assesses the clinical and biochemical effectiveness, and safety of CA in BASDs patients. Methods A systematic review of MEDLINE, Embase and clinical trial registries (ClinicalTrials.gov, ICTRP registry) using controlled MeSH- and Emtree terms. Results From 526 articles 70 publications were deemed eligible for inclusion based on title and abstract. 14 publications were included after full-text assessment comprising case reports and -series with 1–35 patients (162 patients in total) receiving 1 week to 16,5 years of CA treatment. All presented data on effectiveness, 8 studies also presented data on safety. The included population concerned patients with Zellweger spectrum disorders ( n = 73), 3β-Hydroxy-Δ5-C 27 -steroid oxidoreductase deficiency ( n = 62), cerebrotendinous xanthomatosis ( n = 22), Δ4-3-oxosteroid 5β-reductase deficiency ( n = 13), and α-methylacyl-CoA racemase deficiency ( n = 3). Main outcomes concerned liver disease (12 studies), general physical examinations, biochemical outcomes, and safety (9 studies), and fat-soluble vitamin absorption (7 studies). The overall risk of bias score was considered to be critical (1 study), serious (4 studies), and moderate (9 studies). Major issues were missing data (10 studies), generalized data (8 studies), and no wash-out between treatments (4 studies). Conclusion More controlled studies are required as the available data is insufficient to draw definite conclusions on the effectiveness and safety of CA treatment in BASD patients. Establishing an independent international disease registry could better utilize existing real-world data.
Journal of Pediatric Gastroenterology and Nutrition · 1983 · 3 citations
Neonatal Cholestatic Syndromes Associated with Alterations in Bile Acid Synthesis
AbstractIn summary, the conditions discussed above are examples of diseases that result in deficient bile acid synthesis and production of abnormal bile acids. Although the relationship between the production of these abnormal bile acids and the pathogenesis of these diseases remains unknown, they continue to provide us with a better understanding of normal pathways of bile acid production. Clearly, more studies are needed before these interesting metabolic defects and normal infantile bile acid metabolism itself are well understood.
Varied phenotypic presentation of congenital bile acid synthesis defect type 2 in a set of first-degree relatives with the same genetic mutation
AbstractBile acid synthesis disorders represent a rare subset of cholestatic conditions that, if unrecognised, may progress to end-stage liver disease requiring transplantation. These disorders result from deficiencies in one of the 17 enzymes involved in the conversion of cholesterol into primary bile acids. We present a case series of three first-degree relatives diagnosed with congenital bile acid synthesis defect type 2 (AKR1D1 deficiency), a disorder characterised by impaired steroid 5β-reductase activity. After initiating cholic acid, all patients demonstrated significant clinical improvement.
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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