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

¹Centre for Systems Biology, Faculty of Sciences, University of Southern Queensland, Toowoomba, Queensland; and ²Molecular Genetic Therapy Group, Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Nedlands, Perth, Western Australia, Australia

Submitted 23 January 2008 ; accepted in final form 16 May 2008

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.

Duchenne muscular dystrophy; exon skipping; mdx mouse