Assessing the ability of LARGE overexpression to prevent the development of muscular dystrophy

Abstract: Duchenne Muscular Dystrophy (DMD) is a hereditary X-linked fatal disease that affects 1 in 3500 male births. It is the most common kind of muscular dystrophy in children and leads to death in the late teens or early 20s for many patients. The mdx mouse is a model of DMD that can be used to investigate experimental therapies. Overexpression of a glycosyltransferase, CT GalNAc, in mdx mice has been demonstrated to prevent the development of muscular dystrophy. Overexpression of another glycosyltransferase, LARGE, is currently being investigated as a treatment for another group of muscular dystrophies, the dystroglycanopathies. In this study, we overexpressed LARGE in mdx mice in order to investigate its effect on the development of muscular dystrophy. We found that the transgene was expressed in our LV5/mdx mice, as seen with both immunohistochemistry and western blots, but that overexpressing the enzyme unfortunately appeared to have a negative effect on the dystrophy. An increase in pathology was seen histologically at both 3 and 8 weeks of age in the LV5/mdx mice when compared to the mdx mice. Physiological measurements on 22 week old mice showed a significantly diminished tolerance to eccentric exercise in the LV5/mdx compared to their mdx littermates. These observations lead us to the conclusion that increased expression of LARGE is not a therapeutic option for DMD patients, but is in fact contraindicated.