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

• DOI: 10.1038/s41467-018-06008-4
• Publication Date: 2018-08-28T12:09:51Z
• Authors: Prashant K. Sriva...; Jonathan van Eyll; Patrice Godard; Manuela Mazzuferi; Andree Delahaye-D...; Juliette Van Stee...; Pierre Gressens; Benedicte Danis; Catherine Vandenplas; Patrik Foerch; Karine Leclercq; Georges Mairet-Co...; Alvaro Cardenas; Frederic Vanclef; Liisi Laaniste; Isabelle Niespodz...; James Keaney; Julien Gasser; Gaelle Gillet; Kirill Shkura; Seon-Ah Chong; Jacques Behmoaras; Irena Kadiu; Enrico Petretto; Rafal M. Kaminski; Michael R. Johnson
• Keywords: Science; 610; [SDV.GEN] Life Sciences [q-bio]/Genetics; Muscarinic Agonists; DISEASE; Article; Mice; 03 medical and health sciences; Receptors; DRIVERS; Drug Discovery; TEMPORAL-LOBE EPILEPSY; Animals; Humans; Computer Simulation; NETWORK; CELL; EEG; Molecular Targeted Therapy; PILOCARPINE MODEL; Genetic Association Studies; GENE-EXPRESSION; 0303 health sciences; Science & Technology; Epilepsy; Animal; Sequence Analysis, RNA; Gene Expression Profiling; Systems Biology; Q; Pilocarpine; Granulocyte-Macrophage Colony-Stimulating Factor; High-Throughput Nucleotide Sequencing; Temporal Lobe; 3. Good health; Multidisciplinary Sciences; [SDV] Life Sciences [q-bio]; Disease Models, Animal; OPINION; Epilepsy, Temporal Lobe; Gene Expression Regulation; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Disease Models; RNA; Science & Technology - Other Topics; SEIZURES; Anticonvulsants; Sequence Analysis

AbstractThe 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.