CuATSM improves motor function and extends survival but is not tolerated at a high dose in SOD1 G93A mice with a C57BL/6 background

Abstract The synthetic copper-containing compound, CuATSM, has emerged as one of the most promising drug candidates developed for the treatment of amyotrophic lateral sclerosis (ALS). Multiple studies have reported CuATSM treatment provides therapeutic efficacy in various mouse models of ALS without...

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Autores principales:	Jeremy S. Lum, Mikayla L. Brown, Natalie E. Farrawell, Luke McAlary, Diane Ly, Christen G. Chisholm, Josh Snow, Kara L. Vine, Tim Karl, Fabian Kreilaus, Lachlan E. McInnes, Sara Nikseresht, Paul S. Donnelly, Peter J. Crouch, Justin J. Yerbury
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c146cd7fdab24b4d90091d3aa58e739c
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spelling	oai:doaj.org-article:c146cd7fdab24b4d90091d3aa58e739c2021-12-02T17:18:20ZCuATSM improves motor function and extends survival but is not tolerated at a high dose in SOD1 G93A mice with a C57BL/6 background10.1038/s41598-021-98317-w2045-2322https://doaj.org/article/c146cd7fdab24b4d90091d3aa58e739c2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-98317-whttps://doaj.org/toc/2045-2322Abstract The synthetic copper-containing compound, CuATSM, has emerged as one of the most promising drug candidates developed for the treatment of amyotrophic lateral sclerosis (ALS). Multiple studies have reported CuATSM treatment provides therapeutic efficacy in various mouse models of ALS without any observable adverse effects. Moreover, recent results from an open label clinical study suggested that daily oral dosing with CuATSM slows disease progression in patients with both sporadic and familial ALS, providing encouraging support for CuATSM in the treatment of ALS. Here, we assessed CuATSM in high copy SOD1 G93A mice on the congenic C57BL/6 background, treating at 100 mg/kg/day by gavage, starting at 70 days of age. This dose in this specific model has not been assessed previously. Unexpectedly, we report a subset of mice initially administered CuATSM exhibited signs of clinical toxicity, that necessitated euthanasia in extremis after 3–51 days of treatment. Following a 1-week washout period, the remaining mice resumed treatment at the reduced dose of 60 mg/kg/day. At this revised dose, treatment with CuATSM slowed disease progression and increased survival relative to vehicle-treated littermates. This work provides the first evidence that CuATSM produces positive disease-modifying outcomes in high copy SOD1 G93A mice on a congenic C57BL/6 background. Furthermore, results from the 100 mg/kg/day phase of the study support dose escalation determination of tolerability as a prudent step when assessing treatments in previously unassessed models or genetic backgrounds.Jeremy S. LumMikayla L. BrownNatalie E. FarrawellLuke McAlaryDiane LyChristen G. ChisholmJosh SnowKara L. VineTim KarlFabian KreilausLachlan E. McInnesSara NiksereshtPaul S. DonnellyPeter J. CrouchJustin J. YerburyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jeremy S. Lum Mikayla L. Brown Natalie E. Farrawell Luke McAlary Diane Ly Christen G. Chisholm Josh Snow Kara L. Vine Tim Karl Fabian Kreilaus Lachlan E. McInnes Sara Nikseresht Paul S. Donnelly Peter J. Crouch Justin J. Yerbury CuATSM improves motor function and extends survival but is not tolerated at a high dose in SOD1 G93A mice with a C57BL/6 background
description	Abstract The synthetic copper-containing compound, CuATSM, has emerged as one of the most promising drug candidates developed for the treatment of amyotrophic lateral sclerosis (ALS). Multiple studies have reported CuATSM treatment provides therapeutic efficacy in various mouse models of ALS without any observable adverse effects. Moreover, recent results from an open label clinical study suggested that daily oral dosing with CuATSM slows disease progression in patients with both sporadic and familial ALS, providing encouraging support for CuATSM in the treatment of ALS. Here, we assessed CuATSM in high copy SOD1 G93A mice on the congenic C57BL/6 background, treating at 100 mg/kg/day by gavage, starting at 70 days of age. This dose in this specific model has not been assessed previously. Unexpectedly, we report a subset of mice initially administered CuATSM exhibited signs of clinical toxicity, that necessitated euthanasia in extremis after 3–51 days of treatment. Following a 1-week washout period, the remaining mice resumed treatment at the reduced dose of 60 mg/kg/day. At this revised dose, treatment with CuATSM slowed disease progression and increased survival relative to vehicle-treated littermates. This work provides the first evidence that CuATSM produces positive disease-modifying outcomes in high copy SOD1 G93A mice on a congenic C57BL/6 background. Furthermore, results from the 100 mg/kg/day phase of the study support dose escalation determination of tolerability as a prudent step when assessing treatments in previously unassessed models or genetic backgrounds.
format	article
author	Jeremy S. Lum Mikayla L. Brown Natalie E. Farrawell Luke McAlary Diane Ly Christen G. Chisholm Josh Snow Kara L. Vine Tim Karl Fabian Kreilaus Lachlan E. McInnes Sara Nikseresht Paul S. Donnelly Peter J. Crouch Justin J. Yerbury
author_facet	Jeremy S. Lum Mikayla L. Brown Natalie E. Farrawell Luke McAlary Diane Ly Christen G. Chisholm Josh Snow Kara L. Vine Tim Karl Fabian Kreilaus Lachlan E. McInnes Sara Nikseresht Paul S. Donnelly Peter J. Crouch Justin J. Yerbury
author_sort	Jeremy S. Lum
title	CuATSM improves motor function and extends survival but is not tolerated at a high dose in SOD1 G93A mice with a C57BL/6 background
title_short	CuATSM improves motor function and extends survival but is not tolerated at a high dose in SOD1 G93A mice with a C57BL/6 background
title_full	CuATSM improves motor function and extends survival but is not tolerated at a high dose in SOD1 G93A mice with a C57BL/6 background
title_fullStr	CuATSM improves motor function and extends survival but is not tolerated at a high dose in SOD1 G93A mice with a C57BL/6 background
title_full_unstemmed	CuATSM improves motor function and extends survival but is not tolerated at a high dose in SOD1 G93A mice with a C57BL/6 background
title_sort	cuatsm improves motor function and extends survival but is not tolerated at a high dose in sod1 g93a mice with a c57bl/6 background
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c146cd7fdab24b4d90091d3aa58e739c
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CuATSM improves motor function and extends survival but is not tolerated at a high dose in SOD1 G93A mice with a C57BL/6 background

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