Tu141 - HSID: An Integrative Target Discovery Framework for Hidradenitis Suppurativa

Abstract Text: Hidradenitis suppurativa (HS) is a chronic skin condition affecting intertriginous skin areas with apocrine sweat glands. It's characterized by painful, pus-filled bumps that can develop into tunnels beneath the skin. HS causes significant physical and emotional distress due to its recurrent nature, infections, and potential scarring. Current treatments, including TNF and IL-17 blockers, have limited success in resolving the disease, with many patients experiencing flares despite ongoing therapy. Surgical interventions, while sometimes necessary, carry risks and may not fully resolve the condition. These challenges highlight the urgent need for new therapeutic approaches to address HS.

To address this, we developed a comprehensive HS target engine which integrates human genetics data from four GWAS studies totaling over 3100 cases and 940k controls and curated disease mutations from HGMD, 16 bulk and single-cell transcriptomics studies from internal and public datasets, network biology, natural language processing extracted literature data, a knowledge graph, and genome-wide target draggability data. Using this framework, we rank and prioritize every gene by scoring them based on the strength and consistency of the integrated evidence. The top-ranked genes generated by the HS target engine successfully recovers known genes (IL1B, TNF, etc) implicated in HS biology (inflammation, tissue remodeling and destruction, stress responses, etc.) and identifies potential novel targets involved in skin immunity. Notably, clinically validated targets are enriched, with three of the top 20 targets corresponding to approved drugs for HS. This highlights the strength of our framework in uncovering both validated and novel HS therapeutic opportunities.