A systems-level framework for anti-epilepsy drug discovery
File(s)
Accepted version
Supporting information
Author(s)
Johnson, Michael R
Kaminski, Rafal M
Type
Journal Article
Abstract
Modern anti-seizure drug development yielded benefits in terms of improved pharmacokinetics, safety and tolerability profiles, but offered no advances in efficacy compared to previous older generations of anti-seizure drugs. Despite significant advances in our understanding of the genetic bases to epilepsy, and a welcome renewed interest on the severe monogenic epilepsies, modern genetics has yet to directly inform more effective or disease-modifying anti-seizure drugs. Here, we describe a new approach to the identification of novel disease modifying anti-epilepsy drugs. The systems genetics approach aims to first identify pathophysiological mechanisms by integrating polygenic risk with cellular gene expression profiles and then to relate these molecular mechanisms to druggable targets using a gene regulatory (regulome) framework. The approach offers an exciting and flexible framework for future drug discovery in epilepsy, and is applicable to any disease for which appropriate cell-type and disease-context specific data exist.
Date Issued
2019-11-28
Date Acceptance
2019-11-26
Citation
Neuropharmacology, 2019, 170, pp.1-15
ISSN
0028-3908
Publisher
Elsevier
Start Page
1
End Page
15
Journal / Book Title
Neuropharmacology
Volume
170
Copyright Statement
© 2019 Published by Elsevier Ltd. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence http://creativecommons.org/licenses/by-nc-nd/4.0/
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/31785261
PII: S0028-3908(19)30434-4
Subjects
Drug discovery
Epilepsy
Gene regulatory network
Integrative genomics
Network
RNA-seq
Regulome
Systems genetics
Transcriptomics
disease modification
scRNA-seq
single-cell
snRNA-seq
Publication Status
Published online
Coverage Spatial
England
Article Number
ARTN 107868
Date Publish Online
2019-11-28