Gene Editing for Duchenne Muscular Dystrophy Using the CRISPR/Cas9 Technology: The Importance of Fine-tuning the Approach

Tremblay, Jacques P.; Iyombe-Engembe, Jean-Paul; Duchêne, Benjamin; Ouellet, Dominique L.

doi:10.1038/mt.2016.191

Cited by 6 publications

(4 citation statements)

References 14 publications

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“…The ∆Ex50- Dmd -Luc reporter mice described in this study resolve a major challenge associated with the analysis of DMD therapies in mice 28,29 . Because documentation of dystrophin production in vivo necessitated sacrificing animals at different time points, it has not been possible to monitor the impact of therapies over time in the same animal.…”

Section: Discussionmentioning

confidence: 99%

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

Amoasii

Li²,

Zhang³

et al. 2019

Nat Commun

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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.

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Section: Discussionmentioning

confidence: 99%

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

Amoasii

Li²,

Zhang³

et al. 2019

Nat Commun

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“…CRISPR-Cas9 gene editing can target DMD mutations and restore dystrophin expression in mice and muscle cells derived from human induced pluripotent stem cells (iPSCs) (14)(15)(16)(17)(18)(19)(20)(21)(22). An essential step toward clinical translation of gene editing as a therapeutic strategy for DMD is the demonstration of efficacy and safety of this approach in large mammals.…”

mentioning

confidence: 99%

Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy

Amoasii

Hildyard

et al. 2018

Science

445

383

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Mutations in the gene encoding dystrophin, a protein that maintains muscle integrity and function, cause Duchenne muscular dystrophy (DMD). The deltaE50-MD dog model of DMD harbors a mutation corresponding to a mutational “hotspot” in the human DMD gene. We used adeno-associated viruses to deliver CRISPR gene editing components to four dogs and examined dystrophin protein expression 6 weeks after intramuscular delivery (n = 2) or 8 weeks after systemic delivery (n = 2). After systemic delivery in skeletal muscle, dystrophin was restored to levels ranging from 3 to 90% of normal, depending on muscle type. In cardiac muscle, dystrophin levels in the dog receiving the highest dose reached 92% of normal. The treated dogs also showed improved muscle histology. These large-animal data support the concept that, with further development, gene editing approaches may prove clinically useful for the treatment of DMD.

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“…Considering the number of bases in the DNA and the Watson-Crick match, we can replace the A, T, C, G nucleotides with 12 possibilities. Besides, we can also delete and insert more than one nucleotide as in the deletion of the 4 nucleotides in the HEXA gene that caused Tay-Sachs disease (Min et al, 2019[ 90 ]) or exons in DMD (Gadalla et al, 2015[ 36 ]; Tremblay et al, 2016[ 122 ]). What is the success rate in repairing SNPs when such a process is implemented?…”

Section: Mechanisms Of Genome Editing Toolsmentioning

confidence: 99%

Genome editing technologies: CRISPR, LEAPER, RESTORE, ARCUT, SATI, and RESCUE

Yılmaz

2021

EXCLI Journal; 20:Doc19; ISSN 1611-2156

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Gene Editing for Duchenne Muscular Dystrophy Using the CRISPR/Cas9 Technology: The Importance of Fine-tuning the Approach

Cited by 6 publications

References 14 publications

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

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

Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy

Genome editing technologies: CRISPR, LEAPER, RESTORE, ARCUT, SATI, and RESCUE

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