Identification of repurposable cytoprotective drugs in vanishing white matter disease patient-derived cells
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(2020) 5:18
Translational Medicine Communications
RESEARCH
Open Access
Identification of repurposable cytoprotective drugs in vanishing white matter disease patient-derived cells Neville Ng1,2, Mauricio Castro Cabral-da-Silva1,2, Simon Maksour1,3, Tracey Berg1,2, Martin Engel1,2, Dina M. Silva1,2, Dzung Do-Ha1,2, Jeremy S. Lum1,2, Sonia Sanz Muñoz1,2, Nadia Suarez-Bosche1,2, Claire H. Stevens1,2 and Lezanne Ooi1,2*
Abstract Background: Vanishing white matter disease (VWMD) is a rare disease caused by mutations of the guanine exchange factor eIF2B. VWMD typically presents with juvenile onset, and there are few treatments for the disease. Recent progress in the field has established mitochondrial dysfunction and endoplasmic reticulum (ER) stress to be strongly implicated in observed glial cell pathology. Drug repurposing offers a rapid approach toward translation of therapeutics using already-licensed drugs. Objective: The aim of this study was to use fibroblasts and induced pluripotent stem cell (iPSC)-derived astrocytes from patients bearing the EIF2B5R113H/A403V or EIF2B2G200V/E213G VWMD mutations to identify potential repurposable FDA-approved drugs based on in vitro assays. Methods: Cell viability in the presence or absence of stress was assessed by resazurin reduction activity and assays for mitochondrial membrane potential and oxidative stress by tetramethylrhodamine and dichlorofluorescein-based assays, respectively. Integrated stress response markers, including eIF2α phosphorylation, GADD34 and CHOP were quantified by fluorescent western blot. Results: Dysregulated GADD34 and CHOP were identified in patient fibroblasts and iPSC-derived astrocytes under induced stress conditions. A drug screen from a 2400 FDA-approved drug library with EIF2B5R113H/A403V VWMD patient fibroblasts identified 113 anti-inflammatory drugs as a major class of hits with cytoprotective effects. A panel of candidate drugs, including berberine, deflazacort, ursodiol, zileuton, guanabenz and Anavex 2–73, and preclinical ISRIB, increased cell survival of EIF2B5R113H/A403V or EIF2B2G200V/E213G VWMD astrocytes, and were further investigated for their effect on the integrated stress response and mitochondrial stress. Ursodiol demonstrated capacity to ameliorate oxidative stress and loss of mitochondrial membrane potential in VWMD patient iPSC-derived astrocytes in the presence or absence of stress conditions. (Continued on next page)
* Correspondence: [email protected] 1 Illawarra Health and Medical Research Institute, Northfields Avenue, Wollongong, 2522 New South Wales, Australia 2 School of Chemistry and Molecular Bioscience and Molecular Horizons, University of Wollongong, Northfields Avenue, Wollongong, 2522 New South Wales, Australia Full list of author information is available at the end of the article © The Author(s). 2020 Open Access 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
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