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

Nat Commun. 2018 Sep 3;9(1):3561. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants / pharmacology*
  • Computer Simulation
  • Disease Models, Animal
  • Drug Discovery
  • Epilepsy / chemically induced
  • Epilepsy / drug therapy
  • Epilepsy / genetics*
  • Epilepsy, Temporal Lobe / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Genetic Association Studies
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Mice
  • Molecular Targeted Therapy
  • Muscarinic Agonists / toxicity
  • Pilocarpine / toxicity
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / antagonists & inhibitors
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / genetics*
  • Sequence Analysis, RNA
  • Systems Biology


  • Anticonvulsants
  • CSF1R protein, human
  • Csf1r protein, mouse
  • Muscarinic Agonists
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Pilocarpine