PT - JOURNAL ARTICLE AU - Prashant K Srivastava AU - Jonathan van Eyll AU - Patrice Godard AU - Manuela Mazzuferi AU - Benedicte Danis AU - Catherine Vandenplas AU - Patrik Foerch AU - Karine Leclercq AU - Georges Mairet-Coello AU - Frederic Vanclef AU - Kirill Shkura AU - Liisi Laaniste AU - Andree Delahaye-Duriez AU - Rafal M Kaminski AU - Enrico Petretto AU - Michael R Johnson TI - A Systems-Level Framework for Drug Discovery Identifies Csf1R As A Novel Anti-Epileptic Drug Target AID - 10.1101/140087 DP - 2017 Jan 01 TA - bioRxiv PG - 140087 4099 - http://biorxiv.org/content/early/2017/05/22/140087.short 4100 - http://biorxiv.org/content/early/2017/05/22/140087.full AB - 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.