Muscular Dystrophy in Dogs

Miyazato, Lígia Gomes; Moraes, Julieta Rodini Engrácia de; Beretta, Daniel Cortes; Kornegay, Joe N.

doi:10.1177/0300985810387070

Cited by 11 publications

(6 citation statements)

References 29 publications

(47 reference statements)

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“…This negative correlation between body size and phenotype likely reflects stunting rather than cause and effect. We believe the milder clinical signs initially reported in beagle crosses probably reflect the ameliorating effects of outbreeding, as Labrador retrievers with the GRMD mutation also had a less severe phenotype (Miyazato et al 2011). Similarly, in assessing the effects of gender in our own colony, results from phenotypic tests did not differ between homozygous female and heterozygous male GRMD dogs (Kornegay et al 2011).…”

Section: Biomarkers For Assessment Of the Natural History And Responsmentioning

confidence: 92%

Canine models of Duchenne muscular dystrophy and their use in therapeutic strategies

et al. 2012

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Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder in which the loss of dystrophin causes progressive degeneration of skeletal and cardiac muscle. Potential therapies that carry substantial risk, such as gene and cell-based approaches, must first be tested in animal models, notably the mdx mouse and several dystrophin-deficient breeds of dogs, including golden retriever muscular dystrophy (GRMD). Affected dogs have a more severe phenotype, in keeping with that of DMD, so may better predict disease pathogenesis and treatment efficacy. We and others have developed various phenotypic tests to characterize disease progression in the GRMD model. These biomarkers range from measures of strength and joint contractures to magnetic resonance imaging. Some of these tests are routinely used in clinical veterinary practice, while others require specialized equipment and expertise. By comparing serial measurements from treated and untreated groups, one can document improvement or delayed progression of disease. Potential treatments for DMD may be broadly categorized as molecular, cellular, or pharmacologic. The GRMD model has increasingly been used to assess efficacy of a range of these therapies. While some of these studies have largely provided general proof-of-concept for the treatment under study, others have demonstrated efficacy using the biomarkers discussed. Importantly, just as symptoms in DMD vary among patients, GRMD dogs display remarkable phenotypic variation. While confounding statistical analysis in preclinical trials, this variation offers insight regarding the role that modifier genes play in disease pathogenesis. By correlating functional and mRNA profiling results, gene targets for therapy development can be identified.

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Section: Biomarkers For Assessment Of the Natural History And Responsmentioning

confidence: 92%

Canine models of Duchenne muscular dystrophy and their use in therapeutic strategies

et al. 2012

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“…The GRMD mutation has also been crossed to the Beagle background and a colony is now maintained in Japan; these dogs are called canine X-linked muscular dystrophy in Japan or CXMD J ( Shimatsu et al, 2003 ; Valentine et al, 1988 ). Recently, we and others have created hybrid strains that are on mixed genetic backgrounds and/or contain mutations of different breeds ( Cotten et al, 2013 ; Fine et al, 2011 ; Miyazato et al, 2011 ; Shin et al, 2013a ; Yang et al, 2012 ). Besides GRMD-based colonies, research colonies have also been generated from affected Pembroke Welsh corgis and Labrador retrievers (Auburn University and University of Missouri), and CKCS-MD (Royal Veterinary College, UK) ( Smith et al, 2007 ; Smith et al, 2011 ; Walmsley et al, 2010 ).…”

Section: Animal Modeling Of Dystrophin Deficiencymentioning

confidence: 99%

Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy

McGreevy

Hakim

McIntosh

et al. 2015

Disease Models &Amp; Mechanisms

407

401

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Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disorder. It is caused by loss-of-function mutations in the dystrophin gene. Currently, there is no cure. A highly promising therapeutic strategy is to replace or repair the defective dystrophin gene by gene therapy. Numerous animal models of DMD have been developed over the last 30 years, ranging from invertebrate to large mammalian models. mdx mice are the most commonly employed models in DMD research and have been used to lay the groundwork for DMD gene therapy. After ~30 years of development, the field has reached the stage at which the results in mdx mice can be validated and scaled-up in symptomatic large animals. The canine DMD (cDMD) model will be excellent for these studies. In this article, we review the animal models for DMD, the pros and cons of each model system, and the history and progress of preclinical DMD gene therapy research in the animal models. We also discuss the current and emerging challenges in this field and ways to address these challenges using animal models, in particular cDMD dogs.

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“…In some cases, outbreeding may have also contributed to the phenotypic heterogeneity [154]. We have performed a GWAS in our lab using 8 GRMD-affected and 8 age-matched unaffected dogs (including sibling pairs when available).…”

Section: Comparative Genomics Of Grmdmentioning

confidence: 99%

Comparative Genomics of X-linked Muscular Dystrophies: The Golden Retriever Model

Brinkmeyer-Langford

Kornegay

2013

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Duchenne muscular dystrophy (DMD) is a devastating disease that dramatically decreases the lifespan and abilities of affected young people. The primary molecular cause of the disease is the absence of functional dystrophin protein, which is critical to proper muscle function. Those with DMD vary in disease presentation and dystrophin mutation; the same causal mutation may be associated with drastically different levels of disease severity. Also contributing to this variation are the influences of additional modifying genes and/or changes in functional elements governing such modifiers. This genetic heterogeneity complicates the efficacy of treatment methods and to date medical interventions are limited to treating symptoms. Animal models of DMD have been instrumental in teasing out the intricacies of DMD disease and hold great promise for advancing knowledge of its variable presentation and treatment. This review addresses the utility of comparative genomics in elucidating the complex background behind phenotypic variation in a canine model of DMD, Golden Retriever muscular dystrophy (GRMD). This knowledge can be exploited in the development of improved, more personalized treatments for DMD patients, such as therapies that can be tailor-matched to the disease course and genomic background of individual patients.

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Muscular Dystrophy in Dogs

Cited by 11 publications

References 29 publications

Canine models of Duchenne muscular dystrophy and their use in therapeutic strategies

Canine models of Duchenne muscular dystrophy and their use in therapeutic strategies

Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy

Comparative Genomics of X-linked Muscular Dystrophies: The Golden Retriever Model

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