Pig model proves efficacy of exon skipping for Duchenne muscular dystrophy

What is it about?

Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the dystrophin (DMD) gene, leading to complete absence of dystrophin and progressive degeneration of skeletal musculature and myocardium. The majority of DMD mutations are deletions of one or more exons. Frame-shift mutations lead to the formation of a non-functional, truncated dystrophin or the complete absence of dystrophin due to premature stop-codons and - as a consequence - to severe muscular dystrophy. A prominent example is the loss of exon 52, which resembles one of the most frequent DMD mutations in humans. In DMD patients and in the corresponding pig model with a deletion of DMD exon 52, expression of an internally shortened dystrophin can be achieved by skipping of DMD exon 51 to reframe the transcript. However, current delivery strategies for antisense oligonucleotides or gene editing tools limit exon skipping to a proportion of (cardio-)myocytes; the full therapeutic potential remains thus unclear. Therefore, we generated a model of ubiquitous correction of DMD by systemic deletion of exon 51 in the dystrophic pig model lacking DMD exon 52. Molecular, pathological, and clinical alterations were largely rescued, supporting the optimization of exon skipping strategies as a clinically relevant goal.

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Why is it important?

Due to the high susceptibility of pigs to dystrophic muscle lesions, pigs lacking DMD exons 51-52 resemble a form of Becker muscular dystrophy (BMD) and will uncover long-term outcomes within a reasonable time frame.

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