title: Prevention of exercised induced cardiomyopathy following Pip-PMO treatment in dystrophic mdx mice.
abstract: Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder caused by mutations in the Dmd gene. In addition to skeletal muscle wasting, DMD patients develop cardiomyopathy, which significantly contributes to mortality. Antisense oligonucleotides (AOs) are a promising DMD therapy, restoring functional dystrophin protein by exon skipping. However, a major limitation with current AOs is the absence of dystrophin correction in heart. Pip peptide-AOs demonstrate high activity in cardiac muscle. To determine their therapeutic value, dystrophic mdx mice were subject to forced exercise to model the DMD cardiac phenotype. Repeated peptide-AO treatments resulted in high levels of cardiac dystrophin protein, which prevented the exercised induced progression of cardiomyopathy, normalising heart size as well as stabilising other cardiac parameters. Treated mice also exhibited significantly reduced cardiac fibrosis and improved sarcolemmal integrity. This work demonstrates that high levels of cardiac dystrophin restored by Pip peptide-AOs prevents further deterioration of cardiomyopathy and pathology following exercise in dystrophic DMD mice.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.
authors.forename: Corinne A
authors.initials: CA
authors.lastname: Betts
authors.affiliation: 1] Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK [2] AstraZeneca R&D, Discovery Safety, Drug safety and Metabolism, Alderley Park, Macclesfield, SK10 4TG, UK.
authors.forename: Amer F
authors.initials: AF
authors.lastname: Saleh
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Carr
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.
authors.forename: Suzan M
authors.initials: SM
authors.lastname: Hammond
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.
authors.forename: Anna M L
authors.initials: AM
authors.lastname: Coenen-Stass
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.
authors.forename: Caroline
authors.initials: C
authors.lastname: Godfrey
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.
authors.forename: Graham
authors.initials: G
authors.lastname: McClorey
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Varela
authors.affiliation: 1] Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX [2] Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 NTorrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Roberts
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.
authors.forename: Kieran
authors.initials: K
authors.lastname: Clarke
authors.affiliation: Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gait
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.
authors.forename: Matthew J A
authors.initials: MJ
authors.lastname: Wood
mesh_terms: D000818:Animals; D015415:Biomarkers; D009202:Cardiomyopathies / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control / Q000628:therapy; D002311:Cardiomyopathy, Dilated / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control / Q000628:therapy; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D006801:Humans; D019028:Magnetic Resonance Imaging, Cine; D051379:Mice; D018101:Mice, Inbred mdx; D060172:Morpholinos / Q000008:administration & dosage*; D020388:Muscular Dystrophy, Duchenne / Q000150:complications*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D010805:Physical Conditioning, Animal / Q000009:adverse effects*
chemical_list: D015415:Biomarkers; D016189:Dystrophin; D060172:Morpholinos