BACKGROUND: Most human disease definitions, except for rare and communicable diseases, are based on symptoms in specific organs, not on causal molecular mechanisms. This limits treatments to imprecise symptomatic approaches with high numbers needed to treat. Systems medicine, instead, has a holistic approach and defines diseases in an organ-agnostic manner on the basis of associated risk genes, their encoded proteins, and protein-protein interactions. Dysregulation of such disease modules is best corrected by multitarget, synergistic network pharmacology. Here we test this principle in acute ischemic stroke, a highly unmet medical indication without any approved neuroprotective drug so far. METHODS: We extend 3 validated risk genes, neuronal nitric oxide synthase ( RESULTS: We found that a triple-drug combination of a CONCLUSIONS: Our data establish that a mechanism-based network pharmacology approach is effective and clinically safe, warranting a currently ongoing first-in-class neuroprotective phase II interventional trial. REGISTRATION: URL: https://clinicaltrials.gov/study/NCT05762146?term=repo-stroke&rank=1
Unique Identifier: NCT05762146.