Submitted on January 23, 2008
Accepted on May 16, 2008
Long term administration of antisense oligonucleotides into the paraspinal muscles of mdx mice reduces kyphosis
Nicola Laws1, Renee A. Cornford-Nairn2, Nicole Irwin1, Russell Johnsen3, Susan Fletcher3, Stephen D Wilton3, and Andrew J Hoey1*
1 Centre for Systems Biology, University of Southern Queensland, Toowoomba, Queensland, Australia
2 Centre for Systems Biology, University of Southern Queensland, Toowoomba, Queensland, Australia; Centre for Systems Biology, University of Southern Queensland, Toowoomba, Queensland, Australia
3 Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, Western Australia, Australia
* To whom correspondence should be addressed. E-mail: hoey{at}usq.edu.au.
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.
