THERAPEUTIC POTENTIAL OF DYSTROPHIN MINI-GENES

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Duchenne muscular dystrophy (DMD), an X-linked recessive disease caused by mutations in the dystrophin gene, is one of the most common human genetic diseases. Unfortunately, there is no treatment or cure for this lethal disorder. Considerable progress has been made in demonstrating the feasibility of gene therapy for DMD. Nevertheless, numerous issues still need to be addressed before gene therapy can be effectively applied to this common genetic disease. One of the main issues is the limited ability of viral vectors to carry the full-length dystrophin cDNA (14 kb). This application proposes to address this concern by exploring the functional role of the rod domain region through construction of deletion constructs with the ultimate goal of identifying the smallest dystrophin construct that has therapeutic potential. Aim l will test the functional capacity of the Dp260 isoform of dystrophin to reverse the dystrophic phenotype in transgenic mdx (Dystrophin-deficient) mice. The Dp260 cDNA is only 7 kb due to an N- terminal truncation. Aim 2 will explore the actin binding capacity of the Dp260 isoform and rod domain in vitro through solid-phase and co- sedimentation assays. Aim 3 will test various combinations of multiple deletions using transgenic mdx mice in order to find the smallest possible functional dystrophin for delivery via viral vectors. These studies will lead to a greater understanding of the function of dystrophin and will help advance the development of gene therapy for DMD.