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

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Title: A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target
Authors: Srivastava, P
Van Eyll, J
Godard, P
Manuela, M
Delahaye-Duriez, A
Van Steenwinckel, J
Gressens, P
Danis, B
Vandenplas, C
Patrik, F
Leclercq, K
Mairet-Coello, G
Cardenas, A
Vanclef, F
Laaniste, L
Niespodziany, I
Keaney, J
Gasser, J
Gillet, G
Shkura, K
Chong, S-A
Behmoaras, J
Kadiu, I
Petretto, EG
Kaminski, R
Johnson, M
Item Type: Journal Article
Abstract: 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.
Issue Date: 3-Sep-2018
Date of Acceptance: 27-Jul-2018
URI: http://hdl.handle.net/10044/1/62827
DOI: https://dx.doi.org/10.1038/s41467-018-06008-4
ISSN: 2041-1723
Publisher: Nature Publishing Group
Journal / Book Title: Nature Communications
Volume: 9
Copyright Statement: © The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/
Sponsor/Funder: Commission of the European Communities
UCB Biopharma SPRL
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: 602102
4400109351
RDA03
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
TEMPORAL-LOBE EPILEPSY
GENE-EXPRESSION
PILOCARPINE MODEL
EPILEPTOGENESIS
NETWORK
DISEASE
MICE
BIOCONDUCTOR
SEIZURES
DRIVERS
MD Multidisciplinary
Publication Status: Published
Article Number: 3561
Appears in Collections:Clinical Sciences
Molecular Sciences
Department of Medicine
Faculty of Medicine



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