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bioRxiv · 10.1101/140087

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

Srivastava, P. K.·van Eyll, J.·Godard, P.·Mazzuferi, M.·Danis, B.·Vandenplas, C.·Foerch, P.·Leclercq, K.·Mairet-Coello, G.·Vanclef, F.·Shkura, K.·Laaniste, L.·Delahaye-Duriez, A.·Kaminski, R. M.·Petretto, E.·Johnson, M. R.
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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.

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Srivastava, P. K., van Eyll, J., Godard, P., Mazzuferi, M., Danis, B., Vandenplas, C., Foerch, P., Leclercq, K., Mairet-Coello, G., Vanclef, F., Shkura, K., Laaniste, L., Delahaye-Duriez, A., Kaminski, R. M., Petretto, E., Johnson, M. R.. 2017-05-22. A Systems-Level Framework For Drug Discovery Identifies Csf1R As A Novel Anti-Epileptic Drug Target. https://doi.org/10.1101/140087

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