DeCure for Progressive familial intrahepatic cholestasis type 3
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for progressive familial intrahepatic cholestasis type 3 — 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 moduleProgressive familial intrahepatic cholestasis type 3 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 progressive familial intrahepatic cholestasis 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
ATP binding cassette subfamily B member 11 (ABCB11) — ABCB11 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 8PMJ · 2.81 Å · ligand ADENOSINE-5'-TRIPHOSPHATE (ATP). Experimental structure, not a prediction.
What the evidence adds up to
Progressive familial intrahepatic cholestasis type 3 is caused by mutations in the ABCB4 gene and is inherited in an autosomal recessive pattern. About 200 patients with various hepatobiliary disorders linked to ABCB4 mutations have been described in the literature. The disease is a rare disorder of childhood that disrupts bile acid secretion or transport, and it usually progresses to end-stage liver disease within the first two decades of life. A 2024 case series reports two patients from mainland Southeast Asia with a novel homozygous ABCB4 variant (c.779 T > C, p.L260P) whose clinical picture was consistent with cholestasis progressing to end-stage liver disease.
Liver transplant is described as the only curative treatment for progressive familial intrahepatic cholestasis. Biliary diversion surgery is another option for patients without cirrhosis. A retrospective study of nine patients who underwent partial external biliary diversion between 2002 and 2020 found that five required liver transplant during follow-up, four of them due to end-stage liver disease at a median interval of five years. One patient had partial external biliary diversion performed 1.5 years after liver transplant for severe diarrhea, metabolic acidosis, and hepatic steatosis. Four patients did not require liver transplant during follow-up, with a median follow-up time of 7.6 years. Pruritus responded well to the procedure in all patients. Among laboratory values measured six months after biliary diversion, only albumin showed significant improvement. The authors conclude that partial external biliary diversion can relieve pruritus and delay the need for liver transplant, and they consider it the first-line surgical management.
Mutations in genes responsible for familial intrahepatic cholestasis, including ABCB4, ABCB11, TJP2, and NR1H4, can influence serum and hepatic bile acid levels. Experimental studies on NR1H4, which encodes the farnesoid X-activated receptor, suggest that high bile acid concentrations cause excessive production of inflammatory cytokines, resistance to apoptosis, and increased cell regeneration, all conditions that raise the risk of hepatocellular carcinoma and cholangiocarcinoma. Hepatobiliary cancers can emerge in patients with several of these genes. A 2022 review notes that next-generation sequencing and whole-exome sequencing have improved diagnosis and the discovery of responsible genes, and that heterozygous mutations in these genes may cause cryptogenic cholestasis in both young and adult patients.
What remains missing are prospective trials with adequate sample sizes to determine which patients benefit most from biliary diversion versus transplant, and at what stage. The genetic heterogeneity of the disease and the small number of patients make stratification by genotype difficult. Funding for multi-centre registries and long-term follow-up studies is lacking. No drug therapy has been shown to alter the natural history of progressive familial intrahepatic cholestasis type 3.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Cancers · 2022 · 27 citations · open access
Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature
AbstractThe family of inherited intrahepatic cholestasis includes autosomal recessive cholestatic rare diseases of childhood involved in bile acids secretion or bile transport defects. Specific genetic pathways potentially cause many otherwise unexplained cholestasis or hepatobiliary tumours in a healthy liver. Lately, next-generation sequencing and whole-exome sequencing have improved the diagnostic procedures of familial intrahepatic cholestasis (FIC), as well as the discovery of several genes responsible for FIC. Moreover, mutations in these genes, even in the heterozygous status, may be responsible for cryptogenic cholestasis in both young and adults. Mutations in FIC genes can influence serum and hepatic levels of bile acids. Experimental studies on the NR1H4 gene have shown that high bile acids concentrations cause excessive production of inflammatory cytokines, resistance to apoptosis, and increased cell regeneration, all risk conditions for developing hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). NR1H4 gene encodes farnesoid X-activated receptor having a pivotal role in bile salts synthesis. Moreover, HCC and CCA can emerge in patients with several FIC genes such as ABCB11, ABCB4 and TJP2. Herein, we reviewed the available data on FIC-related hepatobiliary cancers, reporting on genetics to the pathophysiology, the risk factors and the clinical presentation.
Postępująca rodzinna cholestaza wewnątrzwątrobowa typu 3
AbstractProgressive familial intrahepatic cholestasis is caused by mutations in the ABCB4 gene and belongs to the family of familial intrahepatic cholestasis disorders inherited in an autosomal recessive pattern. To date, about 200 patients with various hepatobiliary disorders associated with ABCB4 gene mutations have been described in the literature. The aim of this manuscript was to describe the pathogenesis, clinical presentation, diagnostic process and treatment of progressive familial intrahepatic cholestasis type 3, based on the literature review. Keywords: cholestasis, progressive familial intrahepatic cholestasis, ABCB4 gene, MDR3 protein, liver cirrhosis, ursodeoxycholic acid, liver transplantation
Experimental and Clinical Transplantation · 2022 · 1 citations
Partial External Biliary Diversion for Severe Diarrhea After Liver Transplant in Patients with Progressive Familial Intrahepatic Cholestasis Type 1
AbstractProgressive familial intrahepatic cholestasis is a heterogeneous group of autosomal recessive disorders, and liver transplant is the only curative treatment. A biliary diversion operation for disruption of enterohepatic circulation in patients with progressive familial intrahepatic cholestasis type 1 without cirrhosis is another option. We present a pediatric patient with progressive familial intrahepatic cholestasis type 1 who underwent liver transplant due to end-stage liver disease. After transplant, diarrhea and growth retardation complications resolved after partial external biliary diversion surgery.
Experimental and Clinical Transplantation · 2022 · 1 citations
Long-Term Outcomes of Patients With Progressive Familial Intrahepatic Cholestasis After Biliary Diversion
AbstractOBJECTIVES: Progressive familial intrahepatic cholestasis is a heterogeneous group of genetic disorders characterized by disrupted bile homeostasis. Patients with this disease typically present with cholestasis and pruritus early in life and often progress to end-stage liver disease. The clinical symptoms that patients with progressive familial intrahepatic cholestasis encounter are usually refractory to medical treatment. Although the effects of biliary diversion surgery on native liver survival are not exactly known, this procedure may provide a positive impact on pruritus and laboratory parameters in these patients. MATERIALS AND METHODS: We retrospectively evaluated the clinical and laboratory characteristics of patients with progressive familial intrahepatic cholestasis who underwent partial external biliary diversion between 2002 and 2020 at our center. Diagnosis of progressive familial intrahepatic cholestasis was made by clinical, biochemical, and histopathological characteristics as well as genetic testing. RESULTS: Nine patients were included in the study. Five patients required liver transplant during follow-up, with 4 having liver transplant as a result of endstage liver disease (median interval of 5 years). In 1 patient, partial external biliary diversion was performed 1.5 years after liver transplant for severe diarrhea, metabolic acidosis, and hepatic steatosis. Four patients did not require liver transplant during follow-up (median follow-up time of 7.6 years). Pruritus responded well to partial external biliary diversion in all patients. Among laboratory values evaluated 6 months after biliary diversion, only albumin showed significant improvement. CONCLUSIONS: Partial external biliary diversion had favorable results on long-term follow-up. This procedure can provide the relief of pruritus and delay the requirement for liver transplant in patients with progressive familial intrahepatic cholestasis. In our view, partial external biliary diversion should be considered the first-line surgical management for patients with this disease.
A novel genetic variant associated with progressive familial intrahepatic cholestasis type 3: A case series
AbstractProgressive familial intrahepatic cholestasis type 3 (PFIC-3) is a rare disorder characterized by chronic cholestasis usually progressing to end-stage liver disease (ESLD) within the first two decades of life. PFIC-3 is caused by pathogenic genetic variants of the ATP-binding cassette 4 (ABCB4) gene with variable inheritance; the most common is autosomal recessive. We present two cases of PFIC-3 with genetic testing confirming a novel genetic variant in ABCB4 with homozygous genotype c.779 T > C, p.L260P. Both individuals are from mainland Southeast Asia and have a clinical picture consistent with cholestasis progressing to ESLD.
IAR Journal of Medical Case Reports · 2021 · 0 citations · open access
Benign Recurrent Intrahepatic Cholestasis (BRIC): A Case Report in Morocco
AbstractBenign recurrent intrahepatic cholestasis (BRIC) is a rare autosomal recessive inherited disorder characterized by intermittent episodes of severe cholestatic jaundice. After researching the main causes of cholestasis: viral hepatitis, drug and toxic origin, and also eliminate a biliary obstructive cause. Benign recurrent intrahepatic cholestasis (BRIC) is characterized by repeated self-limited episodes of severe pruritus and jaundice that last from several weeks to months. Diagnosis is based on a compatible clinical presentation, laboratory parameters and histology with exclusion of other causes of cholestasis and confirmed by genetic testing. The objective of this clinical case report , is to focus on the diagnostic criteria and to recall the main characteristics concerning BRIC in the literature.
Greater South Information System · 2023 · 0 citations · open access
Genetic alterations and molecular mechanisms underlying hereditary intrahepatic cholestasis
AbstractHereditary cholestatic liver disease caused by a class of autosomal gene mutations results in jaundice, which involves the abnormality of the synthesis, secretion, and other disorders of bile acids metabolism. Due to the existence of a variety of gene mutations, the clinical manifestations of children are also diverse. There is no unified standard for diagnosis and single detection method, which seriously hinders the development of clinical treatment. Therefore, the mutated genes of hereditary intrahepatic cholestasis were systematically described in this review.
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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