Long-term administration of antisense oligonucleotides into the paraspinal muscles of mdx mice reduces kyphosis

Article


Laws, Nicola, Cornford-Nairn, Renee A., Irwin, Nicole, Johnsen, Russell, Fletcher, Susan, Wilton, Stephen D. and Hoey, Andrew J.. 2008. "Long-term administration of antisense oligonucleotides into the paraspinal muscles of mdx mice reduces kyphosis." Journal of Applied Physiology. 105 (2), pp. 662-668. https://doi.org/10.1152/japplphysiol.00068.2008
Article Title

Long-term administration of antisense oligonucleotides into the paraspinal muscles of mdx mice reduces kyphosis

ERA Journal ID3161
Article CategoryArticle
AuthorsLaws, Nicola (Author), Cornford-Nairn, Renee A. (Author), Irwin, Nicole (Author), Johnsen, Russell (Author), Fletcher, Susan (Author), Wilton, Stephen D. (Author) and Hoey, Andrew J. (Author)
Journal TitleJournal of Applied Physiology
Journal Citation105 (2), pp. 662-668
Number of Pages7
Year2008
PublisherAmerican Physiological Society
Place of PublicationUnited States
ISSN1522-1601
8750-7587
Digital Object Identifier (DOI)https://doi.org/10.1152/japplphysiol.00068.2008
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
months 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 months of age (16 months 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.

Keywordsduchenne muscular dystrophy; exon skipping; mdx mouse
ANZSRC Field of Research 2020320905. Neurology and neuromuscular diseases
320601. Gene and molecular therapy
321401. Basic pharmacology
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Byline AffiliationsCentre for Systems Biology
University of Western Australia
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