DeCure for Progressive familial intrahepatic cholestasis type 2
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for progressive familial intrahepatic cholestasis type 2 — 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 2 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 2 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
ATPase phospholipid transporting 8B1 (ATP8B1) — ATP8B1 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 2rdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8OX7 · 2.56 Å · ligand (2R)-3-{[(R)-{[(1S,2S,3R,4S,5S,6S)-2,6-dihydroxy-3,4,5-tris(phosphonooxy)cyclohexyl]oxy}(hydroxy)phosphoryl]oxy}propane
-1,2-diyl dioctanoate (IP9). Experimental structure, not a prediction.
What the evidence adds up to
Progressive familial intrahepatic cholestasis (PFIC) is a chronic condition that begins in childhood and leads to cirrhosis and liver failure in the first years of life. It can be difficult to distinguish from other forms of cholestatic liver disease. Treatment includes medical and surgical methods. One review aimed to describe PFIC in light of recent studies.
PFIC type 2 is caused by mutations in the ABCB4 gene and belongs to the family of familial intrahepatic cholestasis disorders inherited in an autosomal recessive pattern. About 200 patients with various hepatobiliary disorders associated with ABCB4 gene mutations have been described in the literature. A separate review noted that Japanese scholars have proposed that mutation in the gene encoding the tight junction protein 2 (TJP2) may result in PFIC type 4, not type 2.
No clinical trial data, survival figures, or response rates for any drug in PFIC type 2 were reported in these abstracts. The reviews mention ursodeoxycholic acid and liver transplantation as treatments, but provide no efficacy numbers. What is still missing are prospective clinical trials with defined endpoints, patient stratification by genotype, and funding to move beyond literature reviews.
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 Pediatric Gastroenterology and Nutrition · 1997 · 32 citations
Progressive Familial Intrahepatic Cholestasis Among the Arab Population in Israel
AbstractBACKGROUND: Progressive familial intrahepatic cholestasis, which constitutes a heterogeneous group of imperfectly delineated syndromes and appears to be inherited as an autosomal recessive condition, has not been hitherto reported from the Middle East, in spite of the high rate of consanguineous marriage in this region. METHODS: Sixteen affected children from six Israeli Arab families were evaluated over 30 years. All were born to consanguineous parents. RESULTS: Jaundice appeared during the first 3 weeks of life in 15 babies. When first referred, 10 had hepatomegaly and nine had splenomegaly. A progression toward cirrhosis was the rule. Serum levels of conjugated bilirubin, liver enzymes, and alkaline phosphatase were raised; gamma-glutamyl transpeptidase levels were normal in all three infants in whom it was examined, but elevated in two siblings of another family at ages 2 and 3 years. No abnormal bile acids were detected in the serum and urine of patients. Histologic examination of the liver showed giant-cell transformation, paucity of intrahepatic bile ducts, cholestasis, fibrosis, or cirrhosis. The pattern of liver pathology differed at times among affected members within the same family. Therapeutic trials with phenobarbital, cholestyramine, or ursodeoxycholic acid were ineffective. Survival of the patients was from 5 to 18 months in four families; in the other two families, three children received liver transplants, and one is awaiting liver transplantation. CONCLUSIONS: Progressive familial intrahepatic cholestasis should be included in the differential diagnosis of infants with cholestatic jaundice of unknown etiology, especially those born to consanguineous Arab parents.
Frontiers in Pharmacology · 2023 · 15 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.
[Progressive familial intrahepatic cholestasis related to mutation of the TJP2 gene: recent advances].
AbstractProgressive familial intrahepatic cholestasis is a common cause for jaundice and hepatic dysfunction in infancy. Recent studies have provided novel insights into the etiology and pathogenesis of this childhood disease. Japanese scholars have proposed that mutation in the gene encoding the tight junction protein 2 (TJP2) may result in progressive familial intrahepatic cholestasis type 4. Gaining a detailed understanding of the pathogenesis of this disease form, and of its molecular underpinnings, will promote the development of new and more effective diagnostic tools for infantile progressive familial intrahepatic cholestasis.
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
Annals of Gastroenterology and the Digestive System · 2018 · 1 citations · open access
Progressive familial intrahepatic cholestasis in children
AbstractProgressive familial intrahepatic cholestasis (PFIC) is a chronic condition that begin in childhood and leads to cirrhosis and liver failure in the first years of life. It can be difficult to distinguish from other forms of cholestatic liver diseases. Treatment of PFIC includes medical and surgical methods. This study aimed to review PFIC in light of the recent studies.
Indian Journal of Case Reports · 2023 · 0 citations · open access
Benign recurrent intrahepatic cholestasis – case series and literature review
AbstractBenign recurrent intrahepatic cholestasis (BRIC) is a rare form of intrahepatic cholestasis seen in patients with genetic predispositions. It is a rare disease of unknown prevalence and is transmitted as an autosomal recessive pattern of inheritance. The available literature for BRIC is limited. It is hard to formulate the true prevalence of the disorder. Often precipitated by a trigger like viral infections and drugs, this condition results in a self-limiting episode of cholestasis. We present a case series of three patients with the clinical picture of BRIC. All three cases were fully evaluated for the cause of cholestasis and thereafter treated with ursodeoxycholic acid and rifampicin, which showed complete recovery.
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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