Network Proximity-Based Drug Repurposing Strategy for Early and Late Stages of Primary Biliary Cholangitis

Primary biliary cholangitis (PBC) is a chronic, cholestatic, immune-mediated, and progressive liver disorder. Treatment to preventing the disease from advancing into later and irreversible stages is still an unmet clinical need. Accordingly, we set up a drug repurposing framework to find potential therapeutic agents targeting relevant pathways derived from an expanded pool of genes involved in different stages of PBC. Starting with updated human protein-protein interaction data and genes specifically involved in the early and late stages of PBC, a network medicine approach was used to provide a PBC "proximity" or "involvement" gene ranking using network diffusion algorithms and machine learning models. The top genes in the proximity ranking, when combined with the original PBC-related genes, resulted in a final dataset of the genes most involved in PBC disease. Finally, a drug repurposing strategy was implemented by mining and utilizing dedicated drug-gene interaction and druggable genome information knowledge bases (e.g., the DrugBank repository). We identified several potential drug candidates interacting with PBC pathways after performing an over-representation analysis on our initial 1121-seed gene list and the resulting disease-associated (algorithm-obtained) genes. The mechanism and potential therapeutic applications of such drugs were then thoroughly discussed, with a particular emphasis on different stages of PBC disease. We found that interleukin/EGFR/TNF-alpha inhibitors, branched-chain amino acids, geldanamycin, tauroursodeoxycholic acid, genistein, antioestrogens, curcumin, antineovascularisation agents, enzyme/protease inhibitors, and antirheumatic agents are promising drugs targeting distinct stages of PBC. We developed robust and transparent selection mechanisms for prioritizing already approved medicinal products or investigational products for repurposing based on recognized unmet medical needs in PBC, as well as solid preliminary data to achieve this goal.