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Hum Gene Ther. 2018 Jul;29(7):737-748. doi: 10.1089/hum.2017.144. Epub 2018 Mar 22.

Cardiac-Specific Expression of ΔH2-R15 Mini-Dystrophin Normalized All Electrocardiogram Abnormalities and the End-Diastolic Volume in a 23-Month-Old Mouse Model of Duchenne Dilated Cardiomyopathy.

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1 Department of Molecular Microbiology and Immunology, The University of Missouri , Columbia, Missouri.
2 Dubowitz Neuromuscular Centre, Molecular Neurosciences Section, Developmental Neurosciences Programme, UCL Great Ormond Street Institute of Child Health , London, United Kingdom .
3 Department of Neurology, School of Medicine, The University of Missouri , Columbia, Missouri.
4 Department of Bioengineering, The University of Missouri , Columbia, Missouri.
5 Department of Biomedical Sciences, College of Veterinary Medicine, The University of Missouri , Columbia, Missouri.


Heart disease is a major health threat for Duchenne/Becker muscular dystrophy patients and carriers. Expression of a 6-8 kb mini-dystrophin gene in the heart holds promise to change the disease course dramatically. However, the mini-dystrophin gene cannot be easily studied with adeno-associated virus (AAV) gene delivery because the size of the minigene exceeds AAV packaging capacity. Cardiac protection of the ΔH2-R19 minigene was previously studied using the cardiac-specific transgenic approach. Although this minigene fully normalized skeletal muscle force, it only partially corrected electrocardiogram and heart hemodynamics in dystrophin-null mdx mice that had moderate cardiomyopathy. This study evaluated the ΔH2-R15 minigene using the same transgenic approach in mdx mice that had more severe cardiomyopathy. In contrast to the ΔH2-R19 minigene, the ΔH2-R15 minigene carries dystrophin spectrin-like repeats 16 to 19 (R16-19), a region that has been suggested to protect the heart in clinical studies. Cardiac expression of the ΔH2-R15 minigene normalized all aberrant electrocardiogram changes and improved hemodynamics. Importantly, it corrected the end-diastolic volume, an important diastolic parameter not rescued by ΔH2-R19 mini-dystrophin. It is concluded that that ΔH2-R15 mini-dystrophin is a superior candidate gene for heart protection. This finding has important implications in the design of the mini/micro-dystrophin gene for Duchenne cardiomyopathy therapy.


DMD; Duchenne muscular dystrophy; cardiomyopathy; dystrophin; mini-dystrophin; spectrin-like repeat

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