Network Proximity-based Drug Repurposing in COPD

About This Grant

PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide and a major driver of healthcare costs, yet few new therapies have emerged in recent decades. Repurposing existing drugs offers a faster, lower-cost path to treatment; repurposed agents succeed at three times the rate of de novo drugs. Further, drug candidates are twice as likely to be approved when supported by genetic evidence. However, the path to repurposing is often serendipitous rather than systematic. Systematic approaches that utilize genetic and multiple omics data to identify and validate drug repurposing candidates for COPD have not been applied. This project combines network-based computational methods with real-world clinical data to accelerate COPD drug repurposing. In Aim 1, we will build an updated COPD “disease module” by integrating the latest genome- wide association studies and multi-omics data into the human protein interactome. Using a proximity-based framework and hypothesis testing, we will identify drugs whose targets lie closest to COPD-related networks and prioritize those expressed in lung tissue and relevant immune cells. In Aim 2, we will perform comparative effectiveness studies in the Merative Marketscan dataset (>100 million covered lives) to test whether candidate drugs are associated with reduced COPD exacerbations compared to matched referent therapies using state- of- the-art methods for confounding control and causal inference. The expected outcomes include: (1) an updated COPD network module and publicly available web platform for continued repurposing efforts; (2) identification of promising drug candidates with biological plausibility; and (3) prioritization of agents for early-phase clinical trials. This project is innovative in systematically uniting genetics, omics, and network science with pharmacoepidemiology, and significant in contributing to a low-cost, scalable pipeline for drug repurposing in COPD. The work will generate critical preliminary data for subsequent R01 and clinical trial proposals, with the goal of expanding effective treatment options for millions of patients with COPD.