Identification of repurposable cytoprotective drugs in vanishing white matter disease patient-derived cells
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 endoplasm...
Ausführliche Beschreibung
Autor*in: |
Ng, Neville [verfasserIn] Cabral-da-Silva, Mauricio Castro [verfasserIn] Maksour, Simon [verfasserIn] Berg, Tracey [verfasserIn] Engel, Martin [verfasserIn] Silva, Dina M. [verfasserIn] Do-Ha, Dzung [verfasserIn] Lum, Jeremy S. [verfasserIn] Muñoz, Sonia Sanz [verfasserIn] Suarez-Bosche, Nadia [verfasserIn] Stevens, Claire H. [verfasserIn] Ooi, Lezanne [verfasserIn] |
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E-Artikel |
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Sprache: |
Englisch |
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2020 |
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Schlagwörter: |
Vanishing white matter disease |
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Übergeordnetes Werk: |
Enthalten in: Translational medicine communications - [London] : BioMed Central, 2016, 5(2020), 1 vom: 21. Okt. |
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Übergeordnetes Werk: |
volume:5 ; year:2020 ; number:1 ; day:21 ; month:10 |
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DOI / URN: |
10.1186/s41231-020-00071-0 |
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Katalog-ID: |
SPR041489071 |
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520 | |a 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. Conclusion Patient-derived cells can be used to identify cellular phenotypes and for large-scale drug screening. Anti-inflammatory compounds, such as berberine, deflazacort, ursodiol and zileuton are potentially repurposable drug candidates for VWMD that should be further investigated for translation in vivo. | ||
650 | 4 | |a Vanishing white matter disease |7 (dpeaa)DE-He213 | |
650 | 4 | |a Leukodystrophy |7 (dpeaa)DE-He213 | |
650 | 4 | |a Cell stress |7 (dpeaa)DE-He213 | |
650 | 4 | |a Drug repurposing |7 (dpeaa)DE-He213 | |
650 | 4 | |a Induced pluripotent stem cells |7 (dpeaa)DE-He213 | |
650 | 4 | |a Astrocytes |7 (dpeaa)DE-He213 | |
700 | 1 | |a Cabral-da-Silva, Mauricio Castro |e verfasserin |4 aut | |
700 | 1 | |a Maksour, Simon |e verfasserin |4 aut | |
700 | 1 | |a Berg, Tracey |e verfasserin |4 aut | |
700 | 1 | |a Engel, Martin |e verfasserin |4 aut | |
700 | 1 | |a Silva, Dina M. |e verfasserin |4 aut | |
700 | 1 | |a Do-Ha, Dzung |e verfasserin |4 aut | |
700 | 1 | |a Lum, Jeremy S. |e verfasserin |4 aut | |
700 | 1 | |a Muñoz, Sonia Sanz |e verfasserin |4 aut | |
700 | 1 | |a Suarez-Bosche, Nadia |e verfasserin |4 aut | |
700 | 1 | |a Stevens, Claire H. |e verfasserin |4 aut | |
700 | 1 | |a Ooi, Lezanne |e verfasserin |4 aut | |
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10.1186/s41231-020-00071-0 doi (DE-627)SPR041489071 (SPR)s41231-020-00071-0-e DE-627 ger DE-627 rakwb eng 610 ASE 610 ASE Ng, Neville verfasserin aut Identification of repurposable cytoprotective drugs in vanishing white matter disease patient-derived cells 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Conclusion Patient-derived cells can be used to identify cellular phenotypes and for large-scale drug screening. Anti-inflammatory compounds, such as berberine, deflazacort, ursodiol and zileuton are potentially repurposable drug candidates for VWMD that should be further investigated for translation in vivo. Vanishing white matter disease (dpeaa)DE-He213 Leukodystrophy (dpeaa)DE-He213 Cell stress (dpeaa)DE-He213 Drug repurposing (dpeaa)DE-He213 Induced pluripotent stem cells (dpeaa)DE-He213 Astrocytes (dpeaa)DE-He213 Cabral-da-Silva, Mauricio Castro verfasserin aut Maksour, Simon verfasserin aut Berg, Tracey verfasserin aut Engel, Martin verfasserin aut Silva, Dina M. verfasserin aut Do-Ha, Dzung verfasserin aut Lum, Jeremy S. verfasserin aut Muñoz, Sonia Sanz verfasserin aut Suarez-Bosche, Nadia verfasserin aut Stevens, Claire H. verfasserin aut Ooi, Lezanne verfasserin aut Enthalten in Translational medicine communications [London] : BioMed Central, 2016 5(2020), 1 vom: 21. Okt. (DE-627)866576657 (DE-600)2866853-4 2396-832X nnns volume:5 year:2020 number:1 day:21 month:10 https://dx.doi.org/10.1186/s41231-020-00071-0 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 5 2020 1 21 10 |
spelling |
10.1186/s41231-020-00071-0 doi (DE-627)SPR041489071 (SPR)s41231-020-00071-0-e DE-627 ger DE-627 rakwb eng 610 ASE 610 ASE Ng, Neville verfasserin aut Identification of repurposable cytoprotective drugs in vanishing white matter disease patient-derived cells 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Conclusion Patient-derived cells can be used to identify cellular phenotypes and for large-scale drug screening. Anti-inflammatory compounds, such as berberine, deflazacort, ursodiol and zileuton are potentially repurposable drug candidates for VWMD that should be further investigated for translation in vivo. Vanishing white matter disease (dpeaa)DE-He213 Leukodystrophy (dpeaa)DE-He213 Cell stress (dpeaa)DE-He213 Drug repurposing (dpeaa)DE-He213 Induced pluripotent stem cells (dpeaa)DE-He213 Astrocytes (dpeaa)DE-He213 Cabral-da-Silva, Mauricio Castro verfasserin aut Maksour, Simon verfasserin aut Berg, Tracey verfasserin aut Engel, Martin verfasserin aut Silva, Dina M. verfasserin aut Do-Ha, Dzung verfasserin aut Lum, Jeremy S. verfasserin aut Muñoz, Sonia Sanz verfasserin aut Suarez-Bosche, Nadia verfasserin aut Stevens, Claire H. verfasserin aut Ooi, Lezanne verfasserin aut Enthalten in Translational medicine communications [London] : BioMed Central, 2016 5(2020), 1 vom: 21. Okt. (DE-627)866576657 (DE-600)2866853-4 2396-832X nnns volume:5 year:2020 number:1 day:21 month:10 https://dx.doi.org/10.1186/s41231-020-00071-0 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 5 2020 1 21 10 |
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10.1186/s41231-020-00071-0 doi (DE-627)SPR041489071 (SPR)s41231-020-00071-0-e DE-627 ger DE-627 rakwb eng 610 ASE 610 ASE Ng, Neville verfasserin aut Identification of repurposable cytoprotective drugs in vanishing white matter disease patient-derived cells 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Conclusion Patient-derived cells can be used to identify cellular phenotypes and for large-scale drug screening. Anti-inflammatory compounds, such as berberine, deflazacort, ursodiol and zileuton are potentially repurposable drug candidates for VWMD that should be further investigated for translation in vivo. Vanishing white matter disease (dpeaa)DE-He213 Leukodystrophy (dpeaa)DE-He213 Cell stress (dpeaa)DE-He213 Drug repurposing (dpeaa)DE-He213 Induced pluripotent stem cells (dpeaa)DE-He213 Astrocytes (dpeaa)DE-He213 Cabral-da-Silva, Mauricio Castro verfasserin aut Maksour, Simon verfasserin aut Berg, Tracey verfasserin aut Engel, Martin verfasserin aut Silva, Dina M. verfasserin aut Do-Ha, Dzung verfasserin aut Lum, Jeremy S. verfasserin aut Muñoz, Sonia Sanz verfasserin aut Suarez-Bosche, Nadia verfasserin aut Stevens, Claire H. verfasserin aut Ooi, Lezanne verfasserin aut Enthalten in Translational medicine communications [London] : BioMed Central, 2016 5(2020), 1 vom: 21. Okt. (DE-627)866576657 (DE-600)2866853-4 2396-832X nnns volume:5 year:2020 number:1 day:21 month:10 https://dx.doi.org/10.1186/s41231-020-00071-0 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 5 2020 1 21 10 |
allfieldsGer |
10.1186/s41231-020-00071-0 doi (DE-627)SPR041489071 (SPR)s41231-020-00071-0-e DE-627 ger DE-627 rakwb eng 610 ASE 610 ASE Ng, Neville verfasserin aut Identification of repurposable cytoprotective drugs in vanishing white matter disease patient-derived cells 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Conclusion Patient-derived cells can be used to identify cellular phenotypes and for large-scale drug screening. Anti-inflammatory compounds, such as berberine, deflazacort, ursodiol and zileuton are potentially repurposable drug candidates for VWMD that should be further investigated for translation in vivo. Vanishing white matter disease (dpeaa)DE-He213 Leukodystrophy (dpeaa)DE-He213 Cell stress (dpeaa)DE-He213 Drug repurposing (dpeaa)DE-He213 Induced pluripotent stem cells (dpeaa)DE-He213 Astrocytes (dpeaa)DE-He213 Cabral-da-Silva, Mauricio Castro verfasserin aut Maksour, Simon verfasserin aut Berg, Tracey verfasserin aut Engel, Martin verfasserin aut Silva, Dina M. verfasserin aut Do-Ha, Dzung verfasserin aut Lum, Jeremy S. verfasserin aut Muñoz, Sonia Sanz verfasserin aut Suarez-Bosche, Nadia verfasserin aut Stevens, Claire H. verfasserin aut Ooi, Lezanne verfasserin aut Enthalten in Translational medicine communications [London] : BioMed Central, 2016 5(2020), 1 vom: 21. Okt. (DE-627)866576657 (DE-600)2866853-4 2396-832X nnns volume:5 year:2020 number:1 day:21 month:10 https://dx.doi.org/10.1186/s41231-020-00071-0 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 5 2020 1 21 10 |
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10.1186/s41231-020-00071-0 doi (DE-627)SPR041489071 (SPR)s41231-020-00071-0-e DE-627 ger DE-627 rakwb eng 610 ASE 610 ASE Ng, Neville verfasserin aut Identification of repurposable cytoprotective drugs in vanishing white matter disease patient-derived cells 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Conclusion Patient-derived cells can be used to identify cellular phenotypes and for large-scale drug screening. Anti-inflammatory compounds, such as berberine, deflazacort, ursodiol and zileuton are potentially repurposable drug candidates for VWMD that should be further investigated for translation in vivo. Vanishing white matter disease (dpeaa)DE-He213 Leukodystrophy (dpeaa)DE-He213 Cell stress (dpeaa)DE-He213 Drug repurposing (dpeaa)DE-He213 Induced pluripotent stem cells (dpeaa)DE-He213 Astrocytes (dpeaa)DE-He213 Cabral-da-Silva, Mauricio Castro verfasserin aut Maksour, Simon verfasserin aut Berg, Tracey verfasserin aut Engel, Martin verfasserin aut Silva, Dina M. verfasserin aut Do-Ha, Dzung verfasserin aut Lum, Jeremy S. verfasserin aut Muñoz, Sonia Sanz verfasserin aut Suarez-Bosche, Nadia verfasserin aut Stevens, Claire H. verfasserin aut Ooi, Lezanne verfasserin aut Enthalten in Translational medicine communications [London] : BioMed Central, 2016 5(2020), 1 vom: 21. Okt. (DE-627)866576657 (DE-600)2866853-4 2396-832X nnns volume:5 year:2020 number:1 day:21 month:10 https://dx.doi.org/10.1186/s41231-020-00071-0 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 5 2020 1 21 10 |
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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. 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Ng, Neville Cabral-da-Silva, Mauricio Castro Maksour, Simon Berg, Tracey Engel, Martin Silva, Dina M. Do-Ha, Dzung Lum, Jeremy S. Muñoz, Sonia Sanz Suarez-Bosche, Nadia Stevens, Claire H. Ooi, Lezanne |
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10.1186/s41231-020-00071-0 |
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title_sort |
identification of repurposable cytoprotective drugs in vanishing white matter disease patient-derived cells |
title_auth |
Identification of repurposable cytoprotective drugs in vanishing white matter disease patient-derived cells |
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. Conclusion Patient-derived cells can be used to identify cellular phenotypes and for large-scale drug screening. Anti-inflammatory compounds, such as berberine, deflazacort, ursodiol and zileuton are potentially repurposable drug candidates for VWMD that should be further investigated for translation in vivo. |
abstractGer |
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. Conclusion Patient-derived cells can be used to identify cellular phenotypes and for large-scale drug screening. Anti-inflammatory compounds, such as berberine, deflazacort, ursodiol and zileuton are potentially repurposable drug candidates for VWMD that should be further investigated for translation in vivo. |
abstract_unstemmed |
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. Conclusion Patient-derived cells can be used to identify cellular phenotypes and for large-scale drug screening. Anti-inflammatory compounds, such as berberine, deflazacort, ursodiol and zileuton are potentially repurposable drug candidates for VWMD that should be further investigated for translation in vivo. |
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Identification of repurposable cytoprotective drugs in vanishing white matter disease patient-derived cells |
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https://dx.doi.org/10.1186/s41231-020-00071-0 |
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Cabral-da-Silva, Mauricio Castro Maksour, Simon Berg, Tracey Engel, Martin Silva, Dina M. Do-Ha, Dzung Lum, Jeremy S. Muñoz, Sonia Sanz Suarez-Bosche, Nadia Stevens, Claire H. Ooi, Lezanne |
author2Str |
Cabral-da-Silva, Mauricio Castro Maksour, Simon Berg, Tracey Engel, Martin Silva, Dina M. Do-Ha, Dzung Lum, Jeremy S. Muñoz, Sonia Sanz Suarez-Bosche, Nadia Stevens, Claire H. Ooi, Lezanne |
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