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Monitoring disease activity noninvasively in the mdx model of Duchenne muscular dystrophy

A. Filareto,Katie K. Maguire-Nguyen,Qiang Gan,G. Aldanondo,L. Machado,J. Chamberlain,T. Rando

Published 2018 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance Duchenne muscular dystrophy (DMD) is characterized by a catastrophic progression of muscle degeneration that leads to early death. Currently, there is neither a cure for DMD nor any treatments that effectively halt muscle degeneration. Novel methods that assess disease activity non-invasively would greatly accelerate the development of effective therapies. Here we present a novel preclinical animal model that uses bioluminescence imaging as a read-out of muscle degeneration, therefore constituting a non-invasive method to assess disease progression and response to experimental gene therapy in the mdx model of DMD. This model should be widely applicable for monitoring disease activity and responses to therapy in mouse models of muscular dystrophy. Duchenne muscular dystrophy (DMD) is a rare, muscle degenerative disease resulting from the absence of the dystrophin protein. DMD is characterized by progressive loss of muscle fibers, muscle weakness, and eventually loss of ambulation and premature death. Currently, there is no cure for DMD and improved methods of disease monitoring are crucial for the development of novel treatments. In this study, we describe a new method of assessing disease progression noninvasively in the mdx model of DMD. The reporter mice, which we term the dystrophic Degeneration Reporter strains, contain an inducible CRE-responsive luciferase reporter active in mature myofibers. In these mice, muscle degeneration is reflected in changes in the level of luciferase expression, which can be monitored using noninvasive, bioluminescence imaging. We monitored the natural history and disease progression in these dystrophic report mice and found that decreases in luciferase signals directly correlated with muscle degeneration. We further demonstrated that this reporter strain, as well as a previously reported Regeneration Reporter strain, successfully reveals the effectiveness of a gene therapy treatment following systemic administration of a recombinant adeno-associated virus-6 (rAAV-6) encoding a microdystrophin construct. Our data demonstrate the value of these noninvasive imaging modalities for monitoring disease progression and response to therapy in mouse models of muscular dystrophy.

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