The function of dog models in developing gene therapy strategies for human health

Nowend, Keri L.; Starr-Moss, Alison N.; Murphy, Keith E.

doi:10.1007/s00335-011-9348-0

Cited by 19 publications

(14 citation statements)

References 115 publications

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“…– preclinical studies in dog may better predict the potential success of a treatment in humans. In particular, organ size and the immune response in dogs are more similar to those of humans [107]. …”

Section: Animal Modelsmentioning

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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Section: Animal Modelsmentioning

confidence: 99%

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

Brinkmeyer-Langford

Kornegay

2013

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“…Preclinical studies from dogs can predict the potential success of a treatment in humans, as dog models of DMD are genetically and phenotypically comparable to the human disease [16] and, compared to mice, dogs are similar to humans in body and organ size and immune response [17]. Golden retriever muscular dystrophy (GRMD) is the most extensively studied of the canine models of dystrophin-deficient muscular dystrophy.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide association study to identify potential genetic modifiers in a canine model for Duchenne muscular dystrophy

et al. 2016

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BackgroundDuchenne muscular dystrophy (DMD) causes progressive muscle degeneration, cardiomyopathy and respiratory failure in approximately 1/5,000 boys. Golden Retriever muscular dystrophy (GRMD) resembles DMD both clinically and pathologically. Like DMD, GRMD exhibits remarkable phenotypic variation among affected dogs, suggesting the influence of modifiers. Understanding the role(s) of genetic modifiers of GRMD may identify genes and pathways that also modify phenotypes in DMD and reveal novel therapies. Therefore, our objective in this study was to identify genetic modifiers that affect discrete GRMD phenotypes.ResultsWe performed a linear mixed-model (LMM) analysis using 16 variably-affected dogs from our GRMD colony (8 dystrophic, 8 non-dystrophic). All of these dogs were either full or half-siblings, and phenotyped for 19 objective, quantitative biomarkers at ages 6 and 12 months. Each biomarker was individually assessed. Gene expression profiles of 59 possible candidate genes were generated for two muscle types: the cranial tibialis and medial head of the gastrocnemius. SNPs significantly associated with GRMD biomarkers were identified on multiple chromosomes (including the X chromosome). Gene expression levels for candidate genes located near these SNPs correlated with biomarker values, suggesting possible roles as GRMD modifiers.ConclusionsThe results of this study enhance our understanding of GRMD pathology and represent a first step toward the characterization of GRMD modifiers that may be relevant to DMD pathology. Such modifiers are likely to be useful for DMD treatment development based on their relationships to GRMD phenotypes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2948-z) contains supplementary material, which is available to authorized users.

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“…The canine model is also much more cost-effective than primate models. It is a primary preclinical model for hematopoietic stem cell transplantation ((Lupu & Storb 2007)), gene therapy (Nowend et al 2011, Okazuka et al 2011) and cancer research (Gordon & Khanna 2010, Rowell et al 2011). The dog displays a large repertoire of naturally occurring genetic diseases with human counterparts (Athanasiou et al 1995, Lingaas et al 2003, Acland et al 2005) and where data are available, the same genes are involved in both species (Tsai et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Isolation, genetic manipulation, and transplantation of canine spermatogonial stem cells: progress toward transgenesis through the male germ-line

Harkey¹,

Asano²,

Zoulas³

et al. 2013

Reproduction

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The dog is recognized as a highly predictive model for pre-clinical research. Its size, life span, physiology and genetics more closely match human parameters than do those of the mouse model. Investigations of the genetic basis of disease and of new regenerative treatments have frequently taken advantage of canine models. However, full utility of this model hasn’t been realized because of the lack of easy transgenesis. Blastocyst-mediated transgenic technology developed in mice has been very slow to translate to larger animals, and somatic cell nuclear transfer remains technically challenging, expensive, and low yield. Spermatogonial stem cell (SSC) transplantation, which does not involve manipulation of ova or blastocysts, has proven to be an effective alternative approach for generating transgenic offspring in rodents, and in some large animals. Our recent demonstration that canine testis cells can engraft in a host testis, and generate donor-derived sperm, suggests that SSC transplantation may offer a similar avenue to transgenesis in the canine model. Here, we explore the potential of SSC transplantation in dogs as a means of generating canine transgenic models for pre-clinical models of genetic diseases. Specifically, we 1) established markers for identification and tracking canine spermatogonial cells; 2) established methods for enrichment and genetic manipulation of these cells; 3) described their behavior in culture; and 4) demonstrated engraftment of genetically manipulated SSC, and production of transgenic sperm. These findings help set the stage for generation of transgenic canine models via SSC transplantation.

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The function of dog models in developing gene therapy strategies for human health

Cited by 19 publications

References 115 publications

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

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

Genome-wide association study to identify potential genetic modifiers in a canine model for Duchenne muscular dystrophy

Isolation, genetic manipulation, and transplantation of canine spermatogonial stem cells: progress toward transgenesis through the male germ-line

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