In Vivo Transcriptomics-Based Framework for Systematic Indication Expansion

Capturing the systemic effects of drugs in vivo remains a fundamental challenge for drug repurposing strategies. Here, we present an in vivo transcriptomics-based drug repurposing framework that profiles multi-organ RNA-seq from drug-treated rodents to model systemic drug responses and match tissue-specific drug signatures against a compendium of disease signatures for indication expansion. We applied this framework to semaglutide, a GLP-1 receptor agonist originally developed for diabetes and subsequently expanded for several other indications. By harmonizing more than 900 human disease transcriptomic signatures via agentic AI and using Z-transformed reversal of gene expression scoring to quantify drug-disease relationships, our approach successfully recovered established semaglutide indications while deprioritizing Alzheimer’s disease, an indication for which semaglutide was not effective. Top predictions for common diseases were supported by real-world electronic health record data from the Mount Sinai Health System and several predictions for rare indications are proposed for further investigation. This framework provides a scalable strategy for indication expansion across diverse therapeutic agents, especially investigational compounds for which real-world evidence remains sparse.