Dystrophin Levels Required for Genetic Correction of Duchenne Muscular Dystrophy

Correction of the muscle pathology in Duchenne muscular dystrophy (DMD) could theoretically be achieved if methods are developed to produce functional versions of the dystrophin protein in muscle tissue. While a variety of approaches are currently being tested to achieve this aim, we have explored the feasibility of correcting the dystrophic pathology using transgenic mouse model systems. By generating transgenic mice expressing various levels of the muscle isoform of dystrophin in striated muscle we have determined how much dystrophin is needed to prevent the dystrophic pathology. Similarly, we have also explored the use of internally truncated dystrophins that would be of a size that could be inserted into a variety of viral vectors being considered for use in gene therapy protocols. Finally, we have also explored the percentage of muscle fibers that would need to be converted to a dystrophin positive phenotype to achieve a substantial correction of the pathology. The results indicate that a majority of fibers must accumulate approximately 20% of wild-type levels of dystrophin for a significant correction of the muscle pathology.