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Dystrophin-deficient large animal models: translational research and exon skipping
Xinran Yu1, Bo Bao1, Yusuke Echigoya1
1Department of Medical Genetics, School of Human Development, Faculty of Medicine and Dentistry, University of Alberta Edmonton, AB, Canada T6G 2H7.
Abstract:
Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder caused by mutations in the dystrophin gene. Affecting approximately 1 in 3,600-9337 boys, DMD patients exhibit progressive muscle degeneration leading to fatality as a result of heart or respiratory failure. Despite the severity and prevalence of the disease, there is no cure available. While murine models have been successfully used in illustrating the mechanisms of DMD, their utility in DMD research is limited due to their mild disease phenotypes such as lack of severe skeletal muscle and cardiac symptoms. To address the discrepancy between the severity of disease displayed by murine models and human DMD patients, dystrophin-deficient dog models with a splice site mutation in intron 6 were established. Examples of these are Golden Retriever muscular dystrophy and beagle-based Canine X-linked muscular dystrophy. These large animal models are widely employed in therapeutic DMD research due to their close resemblance to the severity of human patient symptoms. Recently, genetically tailored porcine models of DMD with deleted exon 52 were developed by our group and others, and can potentially act as a new large animal model. While therapeutic outcomes derived from these large animal models can be more reliably extrapolated to DMD patients, a comprehensive understanding of these models is still needed. This paper will discuss recent progress and future directions of DMD studies with large animal models such as canine and porcine models.
Insights
Duchenne muscular dystrophy (DMD) research benefits from large animal models like dogs and pigs, which better mimic human disease severity than mice. These models are crucial for advancing potential DMD therapies.
Area of Science:
- Genetics and Molecular Biology
- Animal Models of Disease
- Neuromuscular Disorders
Background:
- Duchenne muscular dystrophy (DMD) is a severe X-linked genetic disorder causing progressive muscle degeneration and fatality.
- Current murine models inadequately replicate human DMD phenotypes, limiting their therapeutic research utility.
- Large animal models offer a more accurate representation of human DMD severity.
Purpose of the Study:
- To review the progress and future directions of Duchenne muscular dystrophy research using large animal models.
- To highlight the advantages of canine and porcine models over murine models for DMD studies.
- To emphasize the need for a comprehensive understanding of these advanced models.
Main Methods:
- Review of existing literature on canine (Golden Retriever muscular dystrophy, Canine X-linked muscular dystrophy) and porcine DMD models.
- Analysis of disease phenotypes in large animal models compared to human patients and murine models.
- Discussion of therapeutic research applications and future potential of these models.
Main Results:
- Dystrophin-deficient dog models exhibit DMD phenotypes closely resembling human patients.
- Genetically engineered porcine models with exon 52 deletion represent a novel large animal model for DMD.
- Large animal models provide more reliable extrapolation of therapeutic outcomes to human DMD patients.
Conclusions:
- Canine and porcine models are valuable tools for Duchenne muscular dystrophy therapeutic research.
- Further comprehensive understanding of these large animal models is essential for maximizing their research potential.
- These models are critical for developing effective Duchenne muscular dystrophy treatments.
