Identification of drug modifiers for RYR1 related myopathy using a multi-species discovery pipeline
Identification of drug modifiers for RYR1 related myopathy using a multi-species discovery pipeline
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.
Dirksen Robert T.、Zuercher William、Noche Ramil、Volpatti Jonathan、Brennan Stephanie、Roy Peter、Dowling James J.、Groom Linda、Endo Yukari
Department of Pharmacology, University of RochesterUNC Eshelman School of Pharmacy, SGC Center for Chemical Biology, University of North Carolina at Chapel HillProgram for Genetics and Genome Biology, Hospital for Sick ChildrenProgram for Genetics and Genome Biology, Hospital for Sick Children||Department of Molecular Genetics, University of TorontoProgram for Genetics and Genome Biology, Hospital for Sick Children||Department of Molecular Genetics, University of TorontoDepartment of Molecular Genetics, University of TorontoProgram for Genetics and Genome Biology, Hospital for Sick Children||Department of Molecular Genetics, University of TorontoDepartment of Pharmacology, University of RochesterProgram for Genetics and Genome Biology, Hospital for Sick Children
医学研究方法基础医学药学
Dirksen Robert T.,Zuercher William,Noche Ramil,Volpatti Jonathan,Brennan Stephanie,Roy Peter,Dowling James J.,Groom Linda,Endo Yukari.Identification of drug modifiers for RYR1 related myopathy using a multi-species discovery pipeline[EB/OL].(2025-03-28)[2025-04-30].https://www.biorxiv.org/content/10.1101/813097.点此复制
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