P28 Identification of novel therapeutic agents in primary sclerosing cholangitis by network proximity analysis

<h3></h3> Primary Sclerosing Cholangitis (PSC) is a progressive cholestatic liver disease with no currently licensed therapies available. There have been multiple Genome Wide Association Studies (GWAS) identifying genes implicated in the disease process, but this is yet to impact therapeutics. We used Network Proximity Analysis (NPA), a novel computational method, to identify drugs known to target genes local to PSC implicated genes. We used 26 unique genes identified from 8 GWAS studies and a previously validated ‘interactome’ network which compared the genes with the freely available DrugBank resource. The outcome is a ‘z-score’, with ≤ -0.15 indicating statistical significance, and a lower score indicating closer proximity (and expected therapeutic effect). This in silico method identified over 2000 significantly implicated drugs, so the most proximal agents were further analysed as possible clinical trial candidates. Of these, 42 were existing medicinal products and 23 already licensed in other products. The most proximal (and therefore likely to have an effect on genetic pathogenesis) drugs were immunomodulatory agents (Denileukin diftitox, -5.087; Basiliximab, -5.038; Abatacept, -3.787; Balatacept, -3.73). The most proximal of the drugs previously trialled in PSC was metronidazole (z-score -2.101). While the demonstrated association does not have directionality, identification of a possible therapeutic drugs in this much under-served group is a promising potential basis for future clinical trials using agents with known safety profiles.