Duchenne and Becker muscular dystrophies (DMD/BMD) are recessively inherited X-linked neuromuscular diseases that result from abnormal expression of the protein dystrophin. A direct approach to treating or curing this disease would be to provide exogenous dystrophin to replace the absent or defective dystrophin in tissues affected by the disease. Gene therapy could be used to provide dystrophin to both muscle and brain cells via delivery of mini-gene vectors containing cloned copies of the dystrophin mRNA. This project will address the feasibility of using gene therapy to treat DMD/BMD by examining whether such an approach can be used to alleviate symptoms in the mdx mouse, an animal model for DMD. The initial goal of this research will be to determine whether dystrophin can be provided via DNAbased techniques to each affected tissue of the mdx mouse: skeletal, cardiac, and smooth muscle as well as the brain. Two approaches will be tested, both of which will utilize mini-gene expression vectors containing full-length murine dystrophin cDNA clones. In the first approach the mini-genes will be microinjected into mouse embryos to create transgenic mice. A variety of gene regulatory elements will be tested, enabling both positive and negative effects of dystrophin expression to be monitored in multiple tissue types. A second and more straightforward approach will involve direct injection of dystrophin minigenes into mdx mouse skeletal muscle. These experiments will address the possibility of delivering dystrophin to muscle without the use of viral vectors or embryo microinjections. Detailed comparisons will be made of physiological abnormalities in mdx muscle as compared with control animals. These experiments will provide the basis for an analysis of whether the exogenous dystrophin is able to assume a functional role. Current assays for effective expression are limited to morphological and immunological determinations. In addition, a variety of altered cDNA constructs will be tested to determine whether cDNA clones shortened by internal truncation are able to encode a functional dystrophin protein. Finally, scanning strategies based upon the polymerase chain reaction will be employed to identify the genetic mutation in two newer strains of mdx mice. Identification of the lesions in these animals will facilitate genetic analyses of dystrophin expression in several mutant strains. These experiments also will reveal whether such scanning methods might be applicable for routine diagnosis of cases of DMD thought to have arisen from point mutations.
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