In vivo non-invasive monitoring of dystrophin correction in a new Duchenne muscular dystrophy reporter mouse

Leonela Amoasii, Hui Li, Yu Zhang, Yi-Li Min, Efrain Sanchez-Ortiz, John M. Shelton, Chengzu Long, Alex A. Mireault, Samadrita Bhattacharyya, John R. McAnally, Rhonda Bassel-Duby and Eric N. Olson ()
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Leonela Amoasii: Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center
Hui Li: Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center
Yu Zhang: Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center
Yi-Li Min: Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center
Efrain Sanchez-Ortiz: Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center
John M. Shelton: University of Texas Southwestern Medical Center
Chengzu Long: Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center
Alex A. Mireault: Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center
Samadrita Bhattacharyya: Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center
John R. McAnally: Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center
Rhonda Bassel-Duby: Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center
Eric N. Olson: Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center

Nature Communications, 2019, vol. 10, issue 1, 1-8

Abstract: Abstract Duchenne muscular dystrophy (DMD) is a fatal genetic disorder caused by mutations in the dystrophin gene. To enable the non-invasive analysis of DMD gene correction strategies in vivo, we introduced a luciferase reporter in-frame with the C-terminus of the dystrophin gene in mice. Expression of this reporter mimics endogenous dystrophin expression and DMD mutations that disrupt the dystrophin open reading frame extinguish luciferase expression. We evaluated the correction of the dystrophin reading frame coupled to luciferase in mice lacking exon 50, a common mutational hotspot, after delivery of CRISPR/Cas9 gene editing machinery with adeno-associated virus. Bioluminescence monitoring revealed efficient and rapid restoration of dystrophin protein expression in affected skeletal muscles and the heart. Our results provide a sensitive non-invasive means of monitoring dystrophin correction in mouse models of DMD and offer a platform for testing different strategies for amelioration of DMD pathogenesis.

Date: 2019
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DOI: 10.1038/s41467-019-12335-x

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