A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target

• Published in: Nature communications Vol. 9; no. 1; pp. 3561 - 15
• Main Authors: Srivastava, Prashant K, van Eyll, Jonathan, Godard, Patrice, Mazzuferi, Manuela, Delahaye-Duriez, Andree, Van Steenwinckel, Juliette, Gressens, Pierre, Danis, Benedicte, Vandenplas, Catherine, Foerch, Patrik, Leclercq, Karine, Mairet-Coello, Georges, Cardenas, Alvaro, Vanclef, Frederic, Laaniste, Liisi, Niespodziany, Isabelle, Keaney, James, Gasser, Julien, Gillet, Gaelle, Shkura, Kirill, Chong, Seon-Ah, Behmoaras, Jacques, Kadiu, Irena, Petretto, Enrico, Kaminski, Rafal M, Johnson, Michael R
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 03.09.2018; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Anticonvulsants - pharmacology; Brain; Computational neuroscience; Computer Simulation; Crafts; Disease Models, Animal; Drug Discovery; Epilepsy; Epilepsy - chemically induced; Epilepsy - drug therapy; Epilepsy - genetics; Epilepsy, Temporal Lobe - genetics; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Genetic Association Studies; Genetics; High-Throughput Nucleotide Sequencing; Humans; Kinases; Life Sciences; Mice; Molecular Targeted Therapy; Muscarinic Agonists - toxicity; Pilocarpine - toxicity; Protein-tyrosine kinase receptors; Reasoning; Receptors; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - antagonists & inhibitors; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Seizures; Sequence Analysis, RNA; Systems Biology; Target recognition; Therapeutic applications; Tyrosine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-06008-4

The identification of drug targets is highly challenging, particularly for diseases of the brain. To address this problem, we developed and experimentally validated a general computational framework for drug target discovery 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 tissue, 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 potential therapeutic target. The predicted effect of Csf1R blockade in attenuating epilepsy seizures was validated in three pre-clinical models of epilepsy. These results highlight CRAFT as a systems-level framework for target discovery and suggest Csf1R blockade as a novel therapeutic strategy in epilepsy. CRAFT is applicable to disease settings other than epilepsy.