Creation of a Novel Humanized Dystrophic Mouse Model of Duchenne Muscular Dystrophy and Application of a CRISPR/Cas9 Gene Editing Therapy

Young, Courtney S.; Mokhonova, Ekaterina; Quiñonez, Marbella; Pyle, April D.; Spencer, Melissa J.

doi:10.3233/jnd-170218

Cited by 77 publications

(73 citation statements)

References 14 publications

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“…Several variations of the CRISPR/Cas9 system have been used, e.g. to generate the hDMD/del45-mdx (Young et al, 2017) and Dmddel8-34 models for DMD (Egorova et al, 2019), and the 521ΔT model for LGMD R5 γ-sarcoglycanrelated (Demonbreun et al, 2019). For the DMD models, guide RNAs were designed to target the region of interest and to guide the Cas9 nuclease to this region to execute the cuts.…”

Section: Targeted Gene Disruptionmentioning

confidence: 99%

“…To allow the use of human-specific sequences when investigating the potential of gene therapies Aartsma-Rus and van Putten, 2020), mice carrying mutations in the human DMD gene have been generated [e.g. with a deletion of exon 45 in hDMD/del45-mdx (Young et al, 2017) or exon 52 in hDMD/del52mdx strains (Veltrop et al, 2018)]. Natural life-history data are not yet available for these new humanized mouse strains, but their pathology appears to be similar to that of the classic mdx mouse (Veltrop et al, 2018;Young et al, 2017).…”

Section: Targeted Gene Disruptionmentioning

confidence: 99%

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Mouse models for muscular dystrophies: an overview

Putten

Lloyd

Greef

et al. 2020

Disease Models &Amp; Mechanisms

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Muscular dystrophies (MDs) encompass a wide variety of inherited disorders that are characterized by loss of muscle tissue associated with a progressive reduction in muscle function. With a cure lacking for MDs, preclinical developments of therapeutic approaches depend on well-characterized animal models that recapitulate the specific pathology in patients. The mouse is the most widely and extensively used model for MDs, and it has played a key role in our understanding of the molecular mechanisms underlying MD pathogenesis. This has enabled the development of therapeutic strategies. Owing to advancements in genetic engineering, a wide variety of mouse models are available for the majority of MDs. Here, we summarize the characteristics of the most commonly used mouse models for a subset of highly studied MDs, collated into a table. Together with references to key publications describing these models, this brief but detailed overview would be useful for those interested in, or working with, mouse models of MD.

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Section: Targeted Gene Disruptionmentioning

confidence: 99%

Section: Targeted Gene Disruptionmentioning

confidence: 99%

Mouse models for muscular dystrophies: an overview

Putten

Lloyd

Greef

et al. 2020

Disease Models &Amp; Mechanisms

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“…the predominantly skeletal muscle-specific Dp427m isoform was expressed at twice the amount in the hDMD mice. The availability of this model enables testing of therapies that rely on the human DMD sequence, such as exon skipping [58] and genome editing [59,60]. A main limitation of this model though is that hDMD mice are phenotypically normal, and thus would not be useful for determining how well a given therapy restores dystrophin synthesis, or improves muscle structure and function.…”

Section: Mousementioning

confidence: 99%

“…Fortunately, CRISPR can be used to edit these hDMD mice, making targeted mutations in the human DMD transgene to create a mutant transcript and cause dystrophin loss. Young et al (2017) generated one such model, with hDMD mice carrying an out-of-frame exon 45 deletion (hDMD del45) [60]. When crossed onto the original mdx or mdxD2 (mdx DBA/2) background, dystrophin was absent in the skeletal muscles and heart by Western blot and immunostaining, save for a few, rare RFs.…”

Section: Mousementioning

confidence: 99%

CRISPR-Generated Animal Models of Duchenne Muscular Dystrophy

Lim

Nguyen

Dzierlega

et al. 2020

Preprint

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Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive neuromuscular disorder most commonly caused by mutations disrupting the reading frame of the dystrophin (DMD) gene. DMD codes for dystrophin, which is critical for maintaining the integrity of muscle cell membranes. Without dystrophin, muscle cells receive heightened mechanical stress, becoming more susceptible to damage. An active body of research continues to explore therapeutic treatments for DMD as well as to further our understanding of the disease. These efforts rely on having reliable animal models that accurately recapitulate disease presentation in humans. While current animal models of DMD have served this purpose quite well, each comes with their own limitations. To help overcome this, clustered regularly interspaced short palindromic repeats (CRISPR)-based technology has been extremely useful in creating novel animal models for DMD. This review focuses on animal models developed for DMD that have been created using CRISPR, their advantages and disadvantages as well as their applications in the DMD field.

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“…On the other hand, humanised mice can also be used as the entire human DMD sequence has been integrated into chromosome 5 of the mouse genome. This enables a more accurate study of disease presentation and treatment of DMD 84. Of course, these animal models will have species-specific differences in clinical course and phenotype of the disease, but will surely be a step forward towards the application of genome editing technology for treatment of DMD in humans 83.…”

Section: Genome Editingmentioning

confidence: 99%

Duchenne muscular dystrophy: genome editing gives new hope for treatment

Crispi

Matsakas

2018

Postgraduate Medical Journal

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Duchenne muscular dystrophy (DMD) is a progressive wasting disease of skeletal and cardiac muscles, representing one of the most common recessive fatal inherited genetic diseases with 1:3500-1:5000 in yearly incidence. It is caused by mutations in the DMD gene that encodes the membrane-associated dystrophin protein. Over the years, many have been the approaches to management of DMD, but despite all efforts, no effective treatment has yet been discovered. Hope for the development of potential therapeutics has followed the recent advances in genome editing and gene therapy. This review gives an overview to DMD and summarises current lines of evidence with regard to treatment and disease management alongside the appropriate considerations.

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Creation of a Novel Humanized Dystrophic Mouse Model of Duchenne Muscular Dystrophy and Application of a CRISPR/Cas9 Gene Editing Therapy

Cited by 77 publications

References 14 publications

Mouse models for muscular dystrophies: an overview

Mouse models for muscular dystrophies: an overview

CRISPR-Generated Animal Models of Duchenne Muscular Dystrophy

Duchenne muscular dystrophy: genome editing gives new hope for treatment

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