title: Long-term administration of antisense oligonucleotides into the paraspinal muscles of mdx mice reduces kyphosis.
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.
authors.affiliation: Centre for Systems Biology, Faculty of Sciences, University of Southern Queensland, Toowoomba, Queensland 4350, Australia.
authors.forename: Nicola
authors.initials: N
authors.lastname: Laws
authors.forename: Renée A
authors.initials: RA
authors.lastname: Cornford-Nairn
authors.forename: Nicole
authors.initials: N
authors.lastname: Irwin
authors.forename: Russell
authors.initials: R
authors.lastname: Johnsen
authors.forename: Susan
authors.initials: S
authors.lastname: Fletcher
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Wilton
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hoey
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D005355:Fibrosis / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006651:Histocytochemistry; D007273:Injections, Intramuscular; D007738:Kyphosis / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009119:Muscle Contraction / Q000502:physiology; D009124:Muscle Proteins / Q000096:biosynthesis / Q000302:isolation & purification; D018482:Muscle, Skeletal / Q000473:pathology / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D012132:Respiratory Muscles / Q000473:pathology; D013131:Spine / Q000502:physiology
chemical_list: D009124:Muscle Proteins; D016376:Oligonucleotides, Antisense