Predictive Network-Medicine Modeling Prioritizes Combinatory Drugs for Amyotrophic Lateral Sclerosis

Abstract Heterogeneity in amyotrophic lateral sclerosis (ALS) pathology has limited the success of monotherapy approaches in clinical trials. We implemented a network-medicine framework integrating ALS signatures with Connectivity Map to identify drug combinations that reverse disease-associated profiles while excluding those that phenocopied ALS. We identified dual targeting of HDAC and ATR kinase pathways may offer a mechanistically convergent therapeutic strategy, demonstrating the potential of network-medicine to prioritize combinatorial therapies for ALS.