Micro-utrophin Improves Cardiac and Skeletal Muscle Function of Severely Affected D2/mdx Mice

Tahnee L Kennedy,Simon Guiraud,Ben Edwards,Sarah Squire,Lee Moir,Arran Babbs,Guy Odom,Diane Golebiowski,Joel Schneider,Jeffrey S Chamberlain,Kay E Davies

doi:10.1016/j.omtm.2018.10.005

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked muscle-wasting disease caused by mutations in the dystrophin gene. DMD boys are wheelchair-bound around 12 years and generally survive into their twenties. There is currently no effective treatment except palliative care, although personalized treatments such as exon skipping, stop codon read-through, and viral-based gene therapies are making progress. Patients present with skeletal muscle pathology, but most also show cardiomyopathy by the age of 10. A systemic therapeutic approach is needed that treats the heart and skeletal muscle defects in all patients. The dystrophin-related protein utrophin has been shown to compensate for the lack of dystrophin in the mildly affected BL10/mdx mouse. The purpose of this investigation was to demonstrate that AAV9-mediated micro-utrophin transgene delivery can not only functionally replace dystrophin in the heart, but also attenuate the skeletal muscle phenotype in severely affected D2/mdx mice. The data presented here show that utrophin can indeed alleviate the pathology in skeletal and cardiac muscle in D2/mdx mice. These results endorse the view that utrophin modulation has the potential to increase the quality life of all DMD patients whatever their mutation.

Highlights

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene leading to the loss of dystrophin, a large structural protein located at the sarcolemma
DMD is primarily recognized as a skeletal muscle disorder, and historically, respiratory muscle insufficiencies accounted for the vast majority of patient deaths.[7]
The data presented here show that associated viral (AAV)-m-Utro administration ameliorates the skeletal and cardiac phenotype of D2/mdx mice, which present with a more severe pathology than the BL10/mdx mouse model due to differences in genetic background.[34,35]

Summary

Introduction

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle-wasting disorder affecting 1:5,000 boys.[1,2,3] DMD is caused by mutations in the dystrophin gene leading to the loss of dystrophin, a large structural protein located at the sarcolemma. The sarcolemma is highly susceptible to contraction-induced injury causing muscle degeneration and replacement of contractile material with adipose and fibrotic tissue.[4,5] These processes typically lead to loss of ambulation between 8 and 12 years, and patients succumb to respiratory and/or cardiac failure in their second or third decade of life.[6] DMD is primarily recognized as a skeletal muscle disorder, and historically, respiratory muscle insufficiencies accounted for the vast majority of patient deaths.[7] with improved disease management, cardiomyopathy has emerged as a leading cause of death in patients receiving assisted ventilation.[8] Despite recent progress and extensive research over the last three decades, there is still no effective treatment for DMD. Development of treatments that target skeletal and cardiac muscle is essential for improving both quality of life and longevity of DMD patients

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Results