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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-09-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-98317-w |
| _version_ | 1818422694873399296 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-14T13:30:20Z |
| format | Article |
| id | doaj.art-c146cd7fdab24b4d90091d3aa58e739c |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T13:30:20Z |
| publishDate | 2021-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-c146cd7fdab24b4d90091d3aa58e739c2022-12-21T22:59:43ZengNature PortfolioScientific Reports2045-23222021-09-0111111210.1038/s41598-021-98317-wCuATSM improves motor function and extends survival but is not tolerated at a high dose in SOD1 G93A mice with a C57BL/6 backgroundJeremy S. Lum0Mikayla L. Brown1Natalie E. Farrawell2Luke McAlary3Diane Ly4Christen G. Chisholm5Josh Snow6Kara L. Vine7Tim Karl8Fabian Kreilaus9Lachlan E. McInnes10Sara Nikseresht11Paul S. Donnelly12Peter J. Crouch13Justin J. Yerbury14Illawarra Health and Medical Research InstituteIllawarra Health and Medical Research InstituteIllawarra Health and Medical Research InstituteIllawarra Health and Medical Research InstituteIllawarra Health and Medical Research InstituteIllawarra Health and Medical Research InstituteSchool of Chemistry and Molecular Bioscience, Molecular Horizons, Faculty of Science, Medicine and Health, University of WollongongIllawarra Health and Medical Research InstituteSchool of Medicine, Western Sydney UniversitySchool of Medicine, Western Sydney UniversitySchool of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of MelbourneDepartment of Biochemistry and Pharmacology, University of MelbourneSchool of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of MelbourneDepartment of Biochemistry and Pharmacology, University of MelbourneIllawarra Health and Medical Research InstituteAbstract 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.https://doi.org/10.1038/s41598-021-98317-w |
| spellingShingle | 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 Scientific Reports |
| 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_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_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_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 |
| url | https://doi.org/10.1038/s41598-021-98317-w |
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