A Systems-Level Framework for Drug Discovery Identifies Csf1R As A Novel Anti-Epileptic Drug Target

ABSTRACT The identification of mechanistically novel drug targets is highly challenging, particularly for diseases of the central nervous system. To address this problem we developed and experimentally validated a new computational approach to drug target identification that combines gene-regulatory information with a causal reasoning framework (“causal reasoning analytical framework for target discovery” – CRAFT). Starting from gene expression data, CRAFT provides a predictive functional genomics framework for identifying membrane receptors with a direction-specified influence over network expression. As proof-of-concept we applied CRAFT to epilepsy, and predicted the tyrosine kinase receptor Csf1R as a novel therapeutic target for epilepsy. The predicted therapeutic effect of Csf1R blockade was validated in two pre-clinical models of epilepsy using a small molecule inhibitor of Csf1R. These results suggest Csf1R blockade as a novel therapeutic strategy in epilepsy, and highlight CRAFT as a systems-level framework for predicting mechanistically new drugs and targets. CRAFT is applicable to disease settings other than epilepsy.