Author + information
- Helena M. Viola, PhDa,
- Victoria P.A. Johnstone, PhDa,
- Abbie M. Adams, BSc Honsb,
- Susan Fletcher, PhDb,c and
- Livia C. Hool, PhDa,d,∗ ()
- aSchool of Human Sciences, The University of Western Australia, Crawley, Western Australia, Australia
- bCentre for Comparative Genomics, Murdoch University, Murdoch, Western Australia, Australia
- cPerron Institute for Neuroscience and Translational Science, and Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, Western Australia, Australia
- dVictor Chang Cardiac Research Institute, Sydney, New South Wales, Australia
- ↵∗Address for correspondence:
Dr. Livia C. Hool, Physiology M311, School of Human Sciences (Physiology), The University of Western Australia, 35 Stirling Highway, Crawley, WA, 6009, Australia.
• DMD patients develop reduced myocardial metabolic activity and dilated cardiomyopathy due to the absence of dystrophin.
• Current clinical trials demonstrate patients receiving PMO therapy exhibit accumulation of functional dystrophin and improved ambulation; however, cardiac abnormalities remain.
• Utilizing the murine model of the disease (mdx), we identify a novel early-intervention PMO treatment regimen for the prevention of DMD cardiomyopathy.
• Pre-cardiomyopathic mdx mice were administered a nontoxic, long-term, high-dose PMO treatment regimen.
• Treated mdx mice exhibited accumulation of functional dystrophin, restoration of cardiac metabolic activity, and did not develop the cardiomyopathy.
Current clinical trials demonstrate Duchenne muscular dystrophy (DMD) patients receiving phosphorodiamidate morpholino oligomer (PMO) therapy exhibit improved ambulation and stable pulmonary function; however, cardiac abnormalities remain. Utilizing the same PMO chemistry as current clinical trials, we have identified a non-toxic PMO treatment regimen that restores metabolic activity and prevents DMD cardiomyopathy. We propose that a treatment regimen of this nature may have the potential to significantly improve morbidity and mortality from DMD by improving ambulation, stabilizing pulmonary function, and preventing the development of cardiomyopathy.
This study was supported by a grant from the National Health and Medical Research Council of Australia and Australian Research Council (1062740). Dr. Viola is supported by a grant from Raine Priming (RPG50). Dr. Hool is a National Health and Medical Research Council Senior Research Fellow (APP1002207). Dr. Fletcher and Ms. Adams were supported by grants from the Muscular Dystrophy Association USA (272200) and the National Health and Medical Research Foundation of Australia (1062740 and 1043758); and receive support from Sarepta Therapeutics. Dr. Fletcher is a consultant to Sarepta Therapeutics; and is named as inventor on patents licensed to Sarepta Therapeutics. The phosphorodiamidate morpholino oligomers used in this study were a gift from Sarepta Therapeutics (Cambridge, Massachusetts) to Sue Fletcher at Murdoch University, for the purpose of investigation of exon skipping and expression of dystrophin in the heart, diaphragm and tibialis anterior. All in vitro and in vivo assessment of cardiac function was performed in the Cardiovascular Electrophysiology Laboratory of Livia Hool at The University of Western Australia, where no financial benefit or research funds were received from Sarepta Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received February 12, 2018.
- Accepted March 15, 2018.
- 2018 The Authors