Using human genomics to validate drug targets for acute ischemic stroke

Sixty years investigating ischemic brain injury mechanisms has yielded more than 1000 drug targets. Yet, not a single cerebroprotective drug has reached FDA approval for the treatment of acute ischemic stroke (AIS), casting doubt on traditional forward-translational approaches. Confirming drug targets using human genomics triples the chances of FDA approval, focusing attention on reverse translational approaches including genome-wide association studies (GWASs). A recent GWAS of 6000 AIS patients using a phenotype of early neurological deterioration/improvement has identified genes implicated in excitotoxicity. This study and others provide proof of principle that GWAS can not only provide human genetic support for existing drug targets but might also identify novel targets for AIS. A challenge with this approach is the identification of key phenotypes that capture mechanisms involved in ischemic brain injury which must be simple, reliable, and scalable. We explore a variety of quantitative phenotypes, many of which are standard of care measures, that will enable future GWASs to study primary and secondary ischemic brain injury. With renewed optimism that cerebroprotection is possible especially when combined with reperfusion therapies, it will be important to increase the odds of success by validating drug targets using genomics and other -omics approaches.