A Morpholino Oligomer Therapy Regime That Restores Mitochondrial Function and Prevents mdx Cardiomyopathy

Helena M Viola; Victoria P A Johnstone; Abbie M Adams; Susan Fletcher; Livia C Hool

doi:10.1016/j.jacbts.2018.03.007

A Morpholino Oligomer Therapy Regime That Restores Mitochondrial Function and Prevents mdx Cardiomyopathy

JACC Basic Transl Sci. 2018 Jun 25;3(3):391-402. doi: 10.1016/j.jacbts.2018.03.007. eCollection 2018 Jun.

Authors

Helena M Viola¹, Victoria P A Johnstone¹, Abbie M Adams², Susan Fletcher^{2

3}, Livia C Hool^{1

4}

Affiliations

¹ School of Human Sciences, The University of Western Australia, Crawley, Western Australia, Australia.
² Centre for Comparative Genomics, Murdoch University, Murdoch, Western Australia, Australia.
³ Perron Institute for Neuroscience and Translational Science, and Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, Western Australia, Australia.
⁴ Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.

Abstract

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.

Keywords: DMD, Duchenne muscular dystrophy; ICa-L, L-type Ca2+ channel; JC-1, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide; L-type calcium channels; PMO, phosphorodiamidate morpholino oligomer; RT-PCR, reverse transcriptase polymerase chain reaction; cardiomyopathy; mdx, murine model of Duchenne muscular dystrophy; mitochondria; wt, wild type; Ψm, mitochondrial membrane potential.