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A systems-level framework for anti-epilepsy drug discovery

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Title: A systems-level framework for anti-epilepsy drug discovery
Authors: Johnson, MR
Kaminski, RM
Item 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.
Issue Date: 28-Nov-2019
Date of Acceptance: 26-Nov-2019
URI: http://hdl.handle.net/10044/1/75471
DOI: 10.1016/j.neuropharm.2019.107868
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/
Keywords: Disease modification
Drug discovery
Epilepsy
Gene regulatory network
Integrative genomics
Network
RNA-seq
Regulome
Single-cell
Systems genetics
Transcriptomics
scRNA-seq
snRNA-seq
Drug discovery
Epilepsy
Gene regulatory network
Integrative genomics
Network
RNA-seq
Regulome
Systems genetics
Transcriptomics
disease modification
scRNA-seq
single-cell
snRNA-seq
Neurology & Neurosurgery
1109 Neurosciences
1115 Pharmacology and Pharmaceutical Sciences
1701 Psychology
Publication Status: Published online
Conference Place: England
Article Number: ARTN 107868
Online Publication Date: 2019-11-28
Appears in Collections:Faculty of Medicine
Department of Brain Sciences