A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target
File(s)
Published version
Author(s)
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.
Date Issued
2018-09-03
Date Acceptance
2018-08-03
Citation
Nature Communications, 2018, 9
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/
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
Commission of the European Communities
UCB Biopharma SPRL
Imperial College Healthcare NHS Trust- BRC Funding
Medical Research Council (MRC)
Medical Research Council (MRC)
Grant Number
602102
4400109351
RDA03
MR/M004716/1
MR/N01121X/1
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
TEMPORAL-LOBE EPILEPSY
GENE-EXPRESSION
PILOCARPINE MODEL
NETWORK
SEIZURES
DRIVERS
OPINION
DISEASE
CELL
EEG
Animals
Anticonvulsants
Computer Simulation
Disease Models, Animal
Drug Discovery
Epilepsy
Epilepsy, Temporal Lobe
Gene Expression Profiling
Gene Expression Regulation
Genetic Association Studies
High-Throughput Nucleotide Sequencing
Humans
Mice
Molecular Targeted Therapy
Muscarinic Agonists
Pilocarpine
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
Sequence Analysis, RNA
Systems Biology
Animals
Humans
Mice
Epilepsy
Epilepsy, Temporal Lobe
Disease Models, Animal
Pilocarpine
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
Muscarinic Agonists
Anticonvulsants
Gene Expression Profiling
Sequence Analysis, RNA
Systems Biology
Gene Expression Regulation
Computer Simulation
Drug Discovery
Genetic Association Studies
Molecular Targeted Therapy
High-Throughput Nucleotide Sequencing
Publication Status
Published
Article Number
3561
Date Publish Online
2018-09-03