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<p>Duchenne muscular dystrophy (DMD) is a devastating X-linked neuromuscular disorder characterized by the absence of a functional dystrophin, leading to progressive muscle loss responsible for cardiorespiratory failure and premature death. While mouse, dog, and pig models have long supported DMD preclinical research, each has limitations in terms of phenotype severity, translational relevance, cost, or ethical acceptance. The emergence of genetically engineered DMD rat models marks a major advancement, offering an intermediate platform that combines practical handling, robust disease features, and disease trajectory accuracy with human patients. Rat models exhibit early, progressive and severe skeletal and cardiac pathology, including impaired muscle regeneration due to satellite cell senescence, all of which closely mirrors patient pathology. In vivo single-nucleus transcriptomics has further highlighted the complexity of fibrotic, inflammatory, and stem cell dysfunction across affected tissues. Importantly, DMD rat models have proven valuable for preclinical therapeutic studies, including gene and exon-skipping therapies, small compounds or cell-based interventions, and senescence-targeting strategies. They have also supported functional, histological, and molecular endpoints aligned with clinical practice. Importantly, DMD rat lines are not phenotypically uniform. Variations in mutation type, involvement of specific dystrophin isoforms, spontaneous exon skipping, and genetic background lead to differences in disease onset, severity, organ involvement, and survival. These distinctions influence the suitability of each model for precision therapeutic strategies. DMD preclinical rat models therefore provide a powerful complementary tool that fits into a continuum of modeling to advance understanding of pathogenic mechanisms, biomarker discovery, and translational research. Their progressive adoption will be accelerating the development of more effective and clinically relevant therapies for patients affected by dystrophin deficiency.</p>

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The rise of rat models for Duchenne muscular dystrophy and therapeutic evaluations

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月17日

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  • Frederic Relaix,
  • Peggy Lafuste,
  • Valentina Taglietti,
  • Laurent Tiret

摘要

Duchenne muscular dystrophy (DMD) is a devastating X-linked neuromuscular disorder characterized by the absence of a functional dystrophin, leading to progressive muscle loss responsible for cardiorespiratory failure and premature death. While mouse, dog, and pig models have long supported DMD preclinical research, each has limitations in terms of phenotype severity, translational relevance, cost, or ethical acceptance. The emergence of genetically engineered DMD rat models marks a major advancement, offering an intermediate platform that combines practical handling, robust disease features, and disease trajectory accuracy with human patients. Rat models exhibit early, progressive and severe skeletal and cardiac pathology, including impaired muscle regeneration due to satellite cell senescence, all of which closely mirrors patient pathology. In vivo single-nucleus transcriptomics has further highlighted the complexity of fibrotic, inflammatory, and stem cell dysfunction across affected tissues. Importantly, DMD rat models have proven valuable for preclinical therapeutic studies, including gene and exon-skipping therapies, small compounds or cell-based interventions, and senescence-targeting strategies. They have also supported functional, histological, and molecular endpoints aligned with clinical practice. Importantly, DMD rat lines are not phenotypically uniform. Variations in mutation type, involvement of specific dystrophin isoforms, spontaneous exon skipping, and genetic background lead to differences in disease onset, severity, organ involvement, and survival. These distinctions influence the suitability of each model for precision therapeutic strategies. DMD preclinical rat models therefore provide a powerful complementary tool that fits into a continuum of modeling to advance understanding of pathogenic mechanisms, biomarker discovery, and translational research. Their progressive adoption will be accelerating the development of more effective and clinically relevant therapies for patients affected by dystrophin deficiency.