Key result
The DmdΔ45 rat model recapitulates key features of Duchenne muscular dystrophy, including progressive muscle degeneration and cardiac dysfunction, though with a milder phenotype due to exon skipping.
Why the study?
Exon 45 deletion is the most frequently reported single exon deletion in DMD patients, motivating the generation of a dedicated animal model to investigate disease mechanisms and therapies.
The novel DmdΔ45 rat model successfully recapitulates the progressive skeletal, cardiac, and cognitive pathologies of Duchenne muscular dystrophy, providing a valuable preclinical tool for testing personalized exon-skipping therapies.
Mutations in the dystrophin (DMD) gene can cause a spectrum of muscle-wasting disorders ranging from the milder Becker muscular dystrophy (BMD) to the more severe Duchenne muscular dystrophy (DMD). Among these, exon 45 deletion is the most frequently reported single exon deletion in DMD patients worldwide. In this study, we generated a novel rat model with an exon 45 deletion using CRISPR/Cas9 technology. The Dmd Δ45 rat recapitulate key clinical and molecular features of DMD, including progressive skeletal muscle degeneration, cardiac dysfunction, cognitive deficits, elevated circulating muscle damage biomarkers, impaired muscle function, and overall reduced lifespan. Transcriptomics analyses confirmed the deletion of exon 45 and revealed gene expression patterns consistent with dystrophin deficiency. In the skeletal muscle, RNA-seq profiles demonstrated a transition from early stress responses and regenerative activity at 6 months to chronic inflammation, fibrosis, and metabolic dysfunction by 12 months. Similarly, the cardiac transcriptomic shifted from an early inflammatory and stress-responsive state to one characterized by fibrotic remodelling and metabolic impairment. Despite these pathological features, the Dmd Δ45 rats exhibited a milder phenotype than other DMD rat models. This attenuation may be attributed to spontaneous exon 44 skipping, which partially restores the reading frame and results in an age-dependent increase in revertant dystrophin-positive fibres. Further analysis indicated downregulation of spliceosome-related genes, suggesting a potential mechanism driving exon skipping in this model. In summary, the Dmd Δ45 rat represents a valuable model for investigating both the molecular determinants of phenotypic variability and the endogenous mechanisms of exon skipping. These findings offer important insights for the development of personalized exon-skipping therapies, particularly for DMD patients with exon 45 deletions.
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Jaber et al. (2025) studied Duchenne muscular dystrophy (n=297). DmdΔ45 genetic mutation vs. Wildtype rats was evaluated on Phenotypic and molecular characterization of the DmdΔ45 rat model. The DmdΔ45 rat model recapitulates key features of Duchenne muscular dystrophy, including progressive muscle degeneration and cardiac dysfunction, though with a milder phenotype due to exon skipping.
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