PR_143: Human Retinal Dystrophin Transgene Prevents Severe Myopathy and Lethality in Duchenne’s Muscular Dystrophy Model Mice

Abstract

Objective: To test the capacity of a naturally occurring isoform, human retinal dystrophin (Dp260), to compensate for the absence of normal muscle dystrophin in a Duchenne’s muscular dystrophy (DMD) mouse model. Design: The most commonly used animal model of DMD is the mdx mouse. This mutant has underlying muscle disease but appears physically normal with an ordinary lifespan, possibly due to compensatory expression of the dystrophin-related protein, utrophin. In contrast, double mutant mice, deficient for both dystrophin and utrophin (mdx, utrn−/−), present a model that truly mimics DMD. These mice die prematurely and demonstrate progressive profound weakness, and spine deformities. A transgene derived from human Dp260 was generated and was driven by a muscle creatine kinase (CK) promoter in the double mutant mouse to assess its application in gene therapy. Setting: Medical institution. Animals: Double mutant mice present a model that clinically resembles DMD. They were compared with double mutant mice with the DP260 transgene, and normal mice for controls. Interventions: Gene therapy of a double mutant mouse model of DMD using a muscle CK promoter-driven human Dp260 transgene. Main Outcome Measures: Outcomes included muscle histology and histochemistry, electromyography, radiographs, magnetic resonance imaging, mobility studies, weight measurement, and lifespan. Results: The transgenic double mutant mice have normal lifespans and normal growth, mobility, and spinal curvature, with improved muscle pathology and electrophysiology. Conclusions: The expression of Dp260 in skeletal muscle prevents premature death and substantially reduces the severe muscular dystrophy to a mild clinical myopathy in the double mutant mouse model. These studies have important clinical implications for the possible treatment of DMD, via gene therapy approaches.