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Published on: May 11, 2018
Long-term administration of antisense oligonucleotides into the paraspinal muscles of mdx mice reduces kyphosis
Nicola Laws1, Renée A Cornford-Nairn, Nicole Irwin
1Centre for Systems Biology, Faculty of Sciences, University of Southern Queensland, Toowoomba, Queensland 4350, Australia.
Abstract:
The mdx mouse model of muscular dystrophy has a premature stop codon preventing production of dystrophin. This results in a progressive phenotype causing centronucleation of skeletal muscle fibers, muscle weakness, and fibrosis and kyphosis. Antisense oligonucleotides alter RNA splicing to exclude the nonsense mutation, while still maintaining the open reading frame to produce a shorter, but partially functional dystrophin protein that should ameliorate the extent of pathology. The present study investigated the benefits of chronic treatment of mdx mice by once-monthly deep intramuscular injections of antisense oligonucleotides into paraspinal muscles. After 8 mo of treatment, mdx mice had reduced development of kyphosis relative to untreated mdx mice, a benefit that was retained until completion of the study at 18 mo of age (16 mo of treatment). This was accompanied by reduced centronucleation in the latissimus dorsi and intercostals muscles and reduced fibrosis in the diaphragm and latissimus dorsi. These benefits were accompanied by a significant increase in dystrophin production. In conclusion, chronic antisense oligonucleotide treatment provides clear and ongoing benefits to paralumbar skeletal muscle, with associated marked reduction in kyphosis.
Insights
Antisense oligonucleotides offer a promising treatment for muscular dystrophy in mdx mice. Chronic treatment reduced kyphosis, muscle fiber changes, and fibrosis, while increasing dystrophin production.
Area of Science:
- Biomedical Science
- Genetics
- Neuromuscular Disorders
Background:
- The mdx mouse model exhibits muscular dystrophy due to a premature stop codon, leading to dystrophin deficiency.
- This deficiency causes progressive skeletal muscle pathology, including centronucleation, weakness, fibrosis, and kyphosis.
Purpose of the Study:
- To investigate the therapeutic benefits of chronic antisense oligonucleotide (ASO) treatment in mdx mice.
- To assess the impact of ASO therapy on kyphosis, muscle pathology, and dystrophin production.
Main Methods:
- mdx mice received monthly deep intramuscular injections of ASOs into paraspinal muscles.
- Treatment duration was 16 months, with assessments at 8 months and study completion at 18 months of age.
- Histological analyses examined centronucleation and fibrosis in various skeletal muscles.
Main Results:
- Chronic ASO treatment significantly reduced the development and progression of kyphosis.
- Reduced centronucleation was observed in the latissimus dorsi and intercostal muscles.
- Decreased fibrosis was noted in the diaphragm and latissimus dorsi muscles, alongside increased dystrophin production.
Conclusions:
- Chronic antisense oligonucleotide treatment demonstrates clear and sustained benefits for paralumbar skeletal muscles in mdx mice.
- ASO therapy effectively ameliorates key pathological features of muscular dystrophy, including kyphosis, muscle fiber abnormalities, and fibrosis.
- The study highlights the potential of ASO-based strategies for treating genetic neuromuscular disorders like muscular dystrophy.
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