Related Experiment Video
Updated: Jan 13, 2026
Multi-exon Skipping Using Cocktail Antisense Oligonucleotides in the Canine X-linked Muscular Dystrophy
Published on: May 24, 2016
A new dystrophin-deficient rat model mirroring exon skipping in patients with DMD exon 45 deletions
Tao Wang1,2, Cynthia Daoud1,2, Auriane Dubois1,2
1Généthon, 91000 Evry France.
Abstract:
Pathogenic variants in the dystrophin (DMD) gene cause muscle-wasting disorders ranging from the milder Becker muscular dystrophy (BMD) to the more severe Duchenne muscular dystrophy (DMD). Exon 45 deletion is the most-frequent single-exon deletion in patients diagnosed with DMD. Here, we generated a novel rat model with an exon 45 deletion using CRISPR/Cas9. The DmdΔ45 rat recapitulate key features of DMD, including progressive skeletal muscle degeneration, impaired muscle and cardiac function, and cognitive deficits. Transcriptomics analyses revealed gene expression patterns consistent with dystrophin deficiency. In skeletal muscle, we observed a transition from early stress responses and regeneration to chronic inflammation, fibrosis and metabolic dysfunction. Cardiac profiles similarly progressed from early inflammatory responses to fibrotic remodelling and metabolic impairment. Notably, DmdΔ45 rats displayed a milder phenotype than other DMD rat models. This attenuation is likely due to spontaneous exon skipping, particularly of exon 44, which partially restores the reading frame and increases revertant dystrophin-positive fibres with age. Downregulation of spliceosome-related genes suggests a potential mechanism for this exon skipping. Overall, this model provides valuable insights into phenotypic variability and therapeutic exon-skipping strategies.
Insights
Researchers created a new rat model for Duchenne muscular dystrophy (DMD) by deleting exon 45 in the dystrophin (DMD) gene. This model shows DMD symptoms and offers insights into disease variability and exon-skipping therapies.
Area of Science:
- Genetics and Molecular Biology
- Animal Models of Disease
- Neuromuscular Disorders
Background:
- Pathogenic variants in the dystrophin (DMD) gene cause Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).
- Exon 45 deletions are the most common single-exon deletions in DMD patients.
- Understanding DMD pathophysiology and developing effective therapies requires accurate animal models.
Purpose of the Study:
- To generate and characterize a novel rat model with an exon 45 deletion in the dystrophin gene using CRISPR/Cas9 technology.
- To investigate the phenotypic features and underlying molecular mechanisms of this new DMD rat model.
- To explore the potential of this model for studying phenotypic variability and evaluating exon-skipping therapeutic strategies.
Main Methods:
- CRISPR/Cas9 gene editing was employed to create an exon 45 deletion in the rat dystrophin (DMD) gene.
- Comprehensive phenotyping included assessments of skeletal muscle, cardiac function, and cognitive abilities.
- Transcriptomics analysis was performed to elucidate gene expression patterns and cellular pathways involved.
Main Results:
- The generated DmdΔ45 rat model recapitulated key features of DMD, including progressive muscle degeneration, impaired cardiac and muscle function, and cognitive deficits.
- Transcriptomic data revealed gene expression profiles consistent with dystrophin deficiency, showing a progression from inflammation and regeneration to fibrosis and metabolic dysfunction in skeletal and cardiac tissues.
- The DmdΔ45 rats exhibited a milder phenotype compared to other DMD rat models, potentially due to spontaneous exon 44 skipping that partially restores the dystrophin reading frame.
Conclusions:
- The novel DmdΔ45 rat model serves as a valuable tool for studying Duchenne muscular dystrophy.
- This model highlights the importance of phenotypic variability in DMD and provides insights into the mechanisms of spontaneous exon skipping.
- The DmdΔ45 rat is suitable for investigating therapeutic exon-skipping strategies for DMD.
