G.P.82: Dystrophin-deficient pigs provide new insights into the hierarchy of physiological derangements of dystrophic muscle

Abstract

Duchenne muscular dystrophy (DMD) is caused by mutations in the X-linked dystrophin (DMD) gene. The absence of dystrophin protein leads to progressive muscle weakness and wasting, disability and death. Existing animal models have been instrumental to understand the pathophysiology of DMD, but have limitations related to the type of mutation, the clinical phenotype, and the predictive value for molecular therapies. To establish a tailored large animal model of DMD, we deleted DMD exon 52 in male pig cells by gene targeting and generated offspring by nuclear transfer. DMD pigs exhibit absence of dystrophin in skeletal muscles, increased serum creatine kinase levels, progressive dystrophic changes of skeletal muscles, impaired mobility, muscle weakness, and a maximum life span of 3 months due to respiratory impairment. These findings render the DMD mutant pig a promising model for testing targeted genetic treatment approaches, such as exon skipping which partially restored in-frame dystrophin gene expression in our model. Regarding recent disappointing results of exon skipping in human DMD clinical trials, a valid animal model will be warranted.