Antisense-mediated exon skipping therapy improves neuromuscular junction deficits in a Duchenne muscular dystrophy mouse model.

Duchenne muscular dystrophy is a muscle wasting disorder caused by lack of dystrophin protein. Dystrophin is present intracellularly at the sarcolemma and is enriched at the postsynaptic membrane of the neuromuscular junction. Morphological and functional neuromuscular junction deficits have been shown in mdx mice, a model lacking dystrophin. Antisense oligonucleotide-mediated exon skipping has been approved in several countries. It is however unclear whether the partial dystrophin restoration achieved is sufficient to rescue muscle functioning. Despite being well investigated at a myofiber level, it is unknown if the exon skipping therapy holds potential to ameliorate or restore neuromuscular junction deficits. This study investigated the effects of exon skipping on the structure and function of the neuromuscular junction in the mdx mouse. On average, restoration of 16 % of wild type dystrophin protein level was achieved in diaphragm muscle following treatment with a 2'-O-methyl phosphorothioate antisense oligonucleotide. This partially improved neuromuscular junction functioning, evidenced by enhanced amplitudes of miniature endplate potentials and endplate potentials, and reduced sensitivity of neuromuscular transmission to the acetylcholine receptor blocker d-tubocurarine, indicating improved synaptic strength. Additionally, aberrant acetylcholine receptor cluster geometry improved.