ena-STUDY-IMPERIAL COLLEGE LONDON-13-07-2018-11:44:24:483-389
Effect of PLX3397 on mouse microglia
The identification of mechanistically novel drug targets is highly challenging, particularly for diseases of the brain. To address this problem, we developed and experimentally validated a new computational approach to drug target identification that combines gene-regulatory information with causal reasoning (“causal reasoning analytical framework for target discovery” – CRAFT). Using a systems genetics approach and starting from gene expression data from the target organ, CRAFT provides a predictive framework for identifying cell membrane receptors with a direction-specified influence over disease-related gene expression profiles. As proof-of-concept, we applied CRAFT to epilepsy and predicted the tyrosine kinase receptor Csf1R as a novel therapeutic target. The predicted therapeutic effect of Csf1R blockade in epilepsy was validated in three pre-clinical models of epilepsy using the small molecule inhibitor of Csf1R PLX3397. These results suggest Csf1R blockade as a novel therapeutic strategy in epilepsy, and highlight CRAFT as a systems-level framework for identifying mechanistically new drugs and targets. CRAFT is applicable to disease settings other than epilepsy. We provide a searchable, interactive database for exploring candidate gene networks for epilepsy and their predicted membrane receptor regulators.
The identification of mechanistically novel drug targets is highly challenging, particularly for diseases of the brain. To address this problem, we developed and experimentally validated a new computational approach to drug target identification that combines gene-regulatory information with causal reasoning (“causal reasoning analytical framework for target discovery” – CRAFT). Using a systems genetics approach and starting from gene expression data from the target organ, CRAFT provides a predictive framework for identifying cell membrane receptors with a direction-specified influence over disease-related gene expression profiles. As proof-of-concept, we applied CRAFT to epilepsy and predicted the tyrosine kinase receptor Csf1R as a novel therapeutic target. The predicted therapeutic effect of Csf1R blockade in epilepsy was validated in three pre-clinical models of epilepsy using the small molecule inhibitor of Csf1R PLX3397. These results suggest Csf1R blockade as a novel therapeutic strategy in epilepsy, and highlight CRAFT as a systems-level framework for identifying mechanistically new drugs and targets. CRAFT is applicable to disease settings other than epilepsy. We provide a searchable, interactive database for exploring candidate gene networks for epilepsy and their predicted membrane receptor regulators.