Network Proximity Analysis As a Theoretical Model for Identifying Potential Novel Therapies in Primary Sclerosing Cholangitis

Overview

Journal BMC Med Genomics

Publisher Biomed Central

Specialty Genetics

Date 2024 Jun 11

PMID 38862968

Authors

Jessica Leighton

David E J Jones

Jessica K Dyson

Heather J Cordell

Affiliations

Soon will be listed here.

Abstract

Primary Sclerosing Cholangitis (PSC) is a progressive cholestatic liver disease with no licensed therapies. Previous Genome Wide Association Studies (GWAS) have identified genes that correlate significantly with PSC, and these were identified by systematic review. Here we use novel Network Proximity Analysis (NPA) methods to identify already licensed candidate drugs that may have an effect on the genetically coded aspects of PSC pathophysiology.Over 2000 agents were identified as significantly linked to genes implicated in PSC by this method. The most significant results include previously researched agents such as metronidazole, as well as biological agents such as basiliximab, abatacept and belatacept. This in silico analysis could potentially serve as a basis for developing novel clinical trials in this rare disease.

References

Tabibian J, Weeding E, Jorgensen R, Petz J, Keach J, Talwalkar J . Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis - a pilot study. Aliment Pharmacol Ther. 2013; 37(6):604-12. DOI: 10.1111/apt.12232. View

Guney E, Menche J, Vidal M, Barabasi A . Network-based in silico drug efficacy screening. Nat Commun. 2016; 7:10331. PMC: 4740350. DOI: 10.1038/ncomms10331. View

Cordell H, Fryett J, Ueno K, Darlay R, Aiba Y, Hitomi Y . An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs. J Hepatol. 2021; 75(3):572-581. PMC: 8811537. DOI: 10.1016/j.jhep.2021.04.055. View

Lindor K, Kowdley K, Luketic V, Harrison M, McCashland T, Befeler A . High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology. 2009; 50(3):808-14. PMC: 2758780. DOI: 10.1002/hep.23082. View

Ellinghaus D, Folseraas T, Holm K, Ellinghaus E, Melum E, Balschun T . Genome-wide association analysis in primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4. Hepatology. 2012; 58(3):1074-83. DOI: 10.1002/hep.25977. View

Cordell H, Han Y, Mells G, Li Y, Hirschfield G, Greene C . International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways. Nat Commun. 2015; 6:8019. PMC: 4580981. DOI: 10.1038/ncomms9019. View

He H, Mennone A, Boyer J, Cai S . Combination of retinoic acid and ursodeoxycholic acid attenuates liver injury in bile duct-ligated rats and human hepatic cells. Hepatology. 2011; 53(2):548-57. PMC: 3069505. DOI: 10.1002/hep.24047. View

Liu J, Hov J, Folseraas T, Ellinghaus E, Rushbrook S, Doncheva N . Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat Genet. 2013; 45(6):670-5. PMC: 3667736. DOI: 10.1038/ng.2616. View

Tabibian J, Gossard A, El-Youssef M, Eaton J, Petz J, Jorgensen R . Prospective Clinical Trial of Rifaximin Therapy for Patients With Primary Sclerosing Cholangitis. Am J Ther. 2014; 24(1):e56-e63. PMC: 4261045. DOI: 10.1097/MJT.0000000000000102. View

10.

Wunsch E, Trottier J, Milkiewicz M, Raszeja-Wyszomirska J, Hirschfield G, Barbier O . Prospective evaluation of ursodeoxycholic acid withdrawal in patients with primary sclerosing cholangitis. Hepatology. 2014; 60(3):931-40. DOI: 10.1002/hep.27074. View

11.

Lindor K . Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med. 1997; 336(10):691-5. DOI: 10.1056/NEJM199703063361003. View

12.

Karlsen T, Franke A, Melum E, Kaser A, Hov J, Balschun T . Genome-wide association analysis in primary sclerosing cholangitis. Gastroenterology. 2009; 138(3):1102-11. DOI: 10.1053/j.gastro.2009.11.046. View

13.

Cheng F, Desai R, Handy D, Wang R, Schneeweiss S, Barabasi A . Network-based approach to prediction and population-based validation of in silico drug repurposing. Nat Commun. 2018; 9(1):2691. PMC: 6043492. DOI: 10.1038/s41467-018-05116-5. View

14.

van Hoogstraten H, Wolfhagen F, van de Meeberg P, Kuiper H, Nix G, Becx M . Ursodeoxycholic acid therapy for primary sclerosing cholangitis: results of a 2-year randomized controlled trial to evaluate single versus multiple daily doses. J Hepatol. 1998; 29(3):417-23. DOI: 10.1016/s0168-8278(98)80059-7. View

15.

Chapman R, Fevery J, Kalloo A, Nagorney D, Boberg K, Shneider B . Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010; 51(2):660-78. DOI: 10.1002/hep.23294. View

16.

Mizuno S, Hirano K, Isayama H, Watanabe T, Yamamoto N, Nakai Y . Prospective study of bezafibrate for the treatment of primary sclerosing cholangitis. J Hepatobiliary Pancreat Sci. 2015; 22(10):766-70. DOI: 10.1002/jhbp.281. View

17.

Cullen S, Rust C, Fleming K, Edwards C, Beuers U, Chapman R . High dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis is safe and effective. J Hepatol. 2008; 48(5):792-800. DOI: 10.1016/j.jhep.2007.12.023. View

18.

Charatcharoenwitthaya P, Angulo P, Enders F, Lindor K . Impact of inflammatory bowel disease and ursodeoxycholic acid therapy on small-duct primary sclerosing cholangitis. Hepatology. 2007; 47(1):133-42. DOI: 10.1002/hep.21960. View

19.

. EASL Clinical Practice Guidelines on sclerosing cholangitis. J Hepatol. 2022; 77(3):761-806. DOI: 10.1016/j.jhep.2022.05.011. View

20.

Ji S, Juran B, Mucha S, Folseraas T, Jostins L, Melum E . Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nat Genet. 2016; 49(2):269-273. PMC: 5540332. DOI: 10.1038/ng.3745. View