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Identification of drug modifiers for RYR1 related myopathy using a multi-species discovery pipeline

Jonathan Volpatti, Yukari Endo, Linda Groom, Stephanie Brennan, Ramil Noche, View ORCID ProfileWilliam Zuercher, Peter Roy, Robert T. Dirksen, James J. Dowling
doi: https://doi.org/10.1101/813097
Jonathan Volpatti
1Program for Genetics and Genome Biology, Hospital for Sick Children, Toronto, CA
2Department of Molecular Genetics, University of Toronto, Toronto, CA
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Yukari Endo
1Program for Genetics and Genome Biology, Hospital for Sick Children, Toronto, CA
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Linda Groom
3Department of Pharmacology, University of Rochester, Rochester, NY, USA
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Stephanie Brennan
1Program for Genetics and Genome Biology, Hospital for Sick Children, Toronto, CA
2Department of Molecular Genetics, University of Toronto, Toronto, CA
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Ramil Noche
1Program for Genetics and Genome Biology, Hospital for Sick Children, Toronto, CA
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William Zuercher
4UNC Eshelman School of Pharmacy, SGC Center for Chemical Biology, University of North Carolina at Chapel Hill, NC, USA
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  • ORCID record for William Zuercher
Peter Roy
2Department of Molecular Genetics, University of Toronto, Toronto, CA
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Robert T. Dirksen
3Department of Pharmacology, University of Rochester, Rochester, NY, USA
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James J. Dowling
1Program for Genetics and Genome Biology, Hospital for Sick Children, Toronto, CA
2Department of Molecular Genetics, University of Toronto, Toronto, CA
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  • For correspondence: james.dowling@sickkids.ca
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Abstract

Ryanodine receptor type I-related myopathies (RYR1-RMs) represent the largest group of non-dystrophic myopathies. RYR1-RMs are associated with severe disabilities and early mortality; despite these facts, there are currently no available treatments. The goal of this study was to identify new therapeutic targets for RYR1-RMs. To accomplish this, we developed a novel discovery pipeline using nematode, zebrafish, and mammalian cell models of the disease. We first performed large-scale drug screens in C. elegans and zebrafish. 74 positive hits were identified in C. elegans, while none were uncovered in the zebrafish. Targeted testing of these hits in zebrafish yielded positive results for two compounds. We examined these compounds using newly created Ryr1 knockout C2C12 cells, and found that p38 inhibition impaired caffeine-induced Ca2+ release. Lastly, we tested one p38 inhibitor in myotubes from Ryr1Y524S/+ (YS) mice, and demonstrated that it blunts the aberrant temperature-dependent increase in resting Ca2+ in these cells. In all, we developed a unique platform for RYR1-RM therapy development that is potentially applicable to a broad range of neuromuscular disorders.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 21, 2019.
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Identification of drug modifiers for RYR1 related myopathy using a multi-species discovery pipeline
Jonathan Volpatti, Yukari Endo, Linda Groom, Stephanie Brennan, Ramil Noche, William Zuercher, Peter Roy, Robert T. Dirksen, James J. Dowling
bioRxiv 813097; doi: https://doi.org/10.1101/813097
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Identification of drug modifiers for RYR1 related myopathy using a multi-species discovery pipeline
Jonathan Volpatti, Yukari Endo, Linda Groom, Stephanie Brennan, Ramil Noche, William Zuercher, Peter Roy, Robert T. Dirksen, James J. Dowling
bioRxiv 813097; doi: https://doi.org/10.1101/813097

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