Generating mouse models for biomedical research: technological advances

Gurumurthy, Channabasavaiah B.; Lloyd, Kevin C K

doi:10.1242/dmm.029462

Cited by 102 publications

(83 citation statements)

References 156 publications

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“…Here, we briefly explain each of these approaches. For more comprehensive reviews on gene-editing techniques for the generation of mouse models, we refer the reader to Gurumurthy and Lloyd (2019), Hall et al (2009) and Justice et al (2011).…”

Section: Technologies To Generate Mouse Models For Mdsmentioning

confidence: 99%

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: Technologies To Generate Mouse Models For Mdsmentioning

confidence: 99%

Mouse models for muscular dystrophies: an overview

Putten

Lloyd

Greef

et al. 2020

Disease Models &Amp; Mechanisms

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“…Initial compound selection requires cell models with corresponding genetic defects. Currently, tools such as induced pluripotent stem cells (iPSCs) and gene-editing technologies such as clustered regularly interspaced short palindromic repeats (CRISPR)/ Cas9 have respectively enabled the rapid production of suitable cell and animal models (Gurumurthy and Lloyd, 2019). The generation of humanized animal models, which recapitulate aspects of the disease pathology and progression and carry the human-specific causative genetic lesion, has become easier in the past decade.…”

Section: Introductionmentioning

confidence: 99%

Moving neuromuscular disorders research forward: from novel models to clinical studies

Putten

Hmeljak

Aartsma‐Rus

et al. 2020

Disease Models &Amp; Mechanisms

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Neuromuscular disorders (NMDs) encompass a diverse group of genetic diseases characterized by loss of muscle functionality. Despite extensive efforts to develop therapies, no curative treatment exists for any of the NMDs. For multiple disorders, however, therapeutic strategies are currently being tested in clinical settings, and the first successful treatments have now entered clinical practice (e.g. spinraza for spinal muscular atrophy). Successful clinical translation depends on the quality and translatability of preclinical findings and on the predictive value of the experimental models used in their initial development. This Special Issue of Disease Models & Mechanisms has a particular focus on translational research for NMDs. The collection includes original research focusing on advances in the development of novel in vitro and in vivo models, broader understanding of disease pathology and progression, and approaches to modify the disease course in these models. We also present a series of special articles and reviews that highlight our understanding of cellular mechanisms, biomarkers to tract disease pathology, the diversity of mouse models for NMDs, the importance of high-quality preclinical studies and data validation, and the pitfalls of successfully moving a potential therapeutic strategy to the clinic. In this Editorial, we summarize the highlights of these articles and place their findings in the broader context of the NMD research field.

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“…To understand the function of a particular gene and its effect on the pathophysiology of a disease, investigators have relied on the generation of animal models where the target gene has been modified or ablated 1 , 2 . While the mouse’s physiology does not fully mimic that of human, the generation of whole-body gene KOs and of tissue conditional knockouts (cKOs) in this species has led to countless discoveries 3 , 4 .…”

Section: Introductionmentioning

confidence: 99%

Generation of a Matrix Gla (Mgp) floxed mouse, followed by conditional knockout, uncovers a new Mgp function in the eye

Borrás

Cowley

Asokan

et al. 2020

Sci Rep

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The ability to ablate a gene in a given tissue by generating a conditional knockout (cKO) is crucial for determining its function in the targeted tissue. Such tissue-specific ablation is even more critical when the gene’s conventional knockout (KO) is lethal, which precludes studying the consequences of its deletion in other tissues. Therefore, here we describe a successful strategy that generated a Matrix Gla floxed mouse (Mgp.floxed) by the CRISPR/Cas9 system, that subsequently allowed the generation of cKOs by local viral delivery of the Cre-recombinase enzyme. MGP is a well-established inhibitor of calcification gene, highly expressed in arteries’ smooth muscle cells and chondrocytes. MGP is also one of the most abundant genes in the trabecular meshwork, the eye tissue responsible for maintenance of intraocular pressure (IOP) and development of Glaucoma. Our strategy entailed one-step injection of two gRNAs, Cas9 protein and a long-single-stranded-circular DNA donor vector (lsscDNA, 6.7 kb) containing two loxP sites in cis and 900–700 bp 5′/3′ homology arms. Ocular intracameral injection of Mgp.floxed mice with a Cre-adenovirus, led to an Mgp.TMcKO mouse which developed elevated IOP. Our study discovered a new role for the Mgp gene as a keeper of physiological IOP in the eye.

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Generating mouse models for biomedical research: technological advances

Cited by 102 publications

References 156 publications

Mouse models for muscular dystrophies: an overview

Mouse models for muscular dystrophies: an overview

Moving neuromuscular disorders research forward: from novel models to clinical studies

Generation of a Matrix Gla (Mgp) floxed mouse, followed by conditional knockout, uncovers a new Mgp function in the eye

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