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

Laws, Nicola and Cornford-Nairn, Renee A. and Irwin, Nicole and Johnsen, Russell and Fletcher, Susan and 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. ISSN 8750-7587


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.

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Item Type: Article (Commonwealth Reporting Category C)
Refereed: Yes
Item Status: Live Archive
Additional Information: Permanenet restricted access to paper due to publisher copyright restrictions.
Faculty / Department / School: Historic - Faculty of Sciences - Department of Biological and Physical Sciences
Date Deposited: 22 Jun 2009 11:42
Last Modified: 16 Oct 2014 00:58
Uncontrolled Keywords: duchenne muscular dystrophy; exon skipping; mdx mouse
Fields of Research : 11 Medical and Health Sciences > 1109 Neurosciences > 110904 Neurology and Neuromuscular Diseases
10 Technology > 1004 Medical Biotechnology > 100401 Gene and Molecular Therapy
11 Medical and Health Sciences > 1115 Pharmacology and Pharmaceutical Sciences > 111501 Basic Pharmacology
Socio-Economic Objective: E Expanding Knowledge > 97 Expanding Knowledge > 970111 Expanding Knowledge in the Medical and Health Sciences
Identification Number or DOI: 10.1152/japplphysiol.00068.2008
URI: http://eprints.usq.edu.au/id/eprint/5096

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