RT Journal Article
SR Electronic
T1 A Systems-Level Framework for Drug Discovery Identifies Csf1R As A Novel Anti-Epileptic Drug Target
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 140087
DO 10.1101/140087
A1 Prashant K Srivastava
A1 Jonathan van Eyll
A1 Patrice Godard
A1 Manuela Mazzuferi
A1 Benedicte Danis
A1 Catherine Vandenplas
A1 Patrik Foerch
A1 Karine Leclercq
A1 Georges Mairet-Coello
A1 Frederic Vanclef
A1 Kirill Shkura
A1 Liisi Laaniste
A1 Andree Delahaye-Duriez
A1 Rafal M Kaminski
A1 Enrico Petretto
A1 Michael R Johnson
YR 2017
UL http://biorxiv.org/content/early/2017/05/22/140087.abstract
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.