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- Title
CRAFTing a New Approach to Antiepileptic Drug Discovery.
- Authors
Lyman, Kyle A.; Chetkovich, Dane M.
- Abstract
Srivastava PK, van Eyll J, Godard P, Mazzuferi M, Delahaye-Duriez A, Steenwinckel JV, et al. A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target. Nat Commun. 2018;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 3 preclinical 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. The CRAFT is applicable to disease settings other than epilepsy.
- Subjects
CELL receptors; ANTICONVULSANTS; GENE expression profiling; REGULATOR genes; PROTEIN-tyrosine kinases
- Publication
Epilepsy Currents, 2019, Vol 19, Issue 3, p182
- ISSN
1535-7597
- Publication type
Article
- DOI
10.1177/1535759719842148