Glycosyltransferase Therapy for Myopathies

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DESCRIPTION (provided by applicant): Muscular Dystrophy is a serious health problem in the United States and throughout the world. While the genetic basis underlying many forms of muscular dystrophy is known, therapies for these disorders remain elusive. The most common genetic form of muscular dystrophy is Duchenne muscular dystrophy (DMD), an X-linked disorder that afflicts roughly one in every 3500 boys. Our laboratory has identified a novel means of inhibiting the dystrophic process from developing in mdx mice, a model for DMD. This involves the overexpression of a glycosyltransferase called the CT GalNAc transferase, either using transgenic or gene therapy approaches. This proposal seeks to characterize the mechanism by which the CT GalNAc transferase (CT) inhibits muscular dystrophy. The first aim will test whether overexpression of utrophin, a dystrophy-sparing protein, is required for inhibition of muscular dystrophy in CT transgenic mdx mice. The second aim will determine if increased expression of utrophin and extracellular matrix proteins in CT transgenic mdx muscles occurs via changes in protein affinity for dystroglycan, the major protein glycosylated with the CT carbohydrate in skeletal muscle. The third aim will test whether increased expression of the CT GalNAc transferase inhibits the development of muscular dystrophy in models for two forms of congenital muscular dystrophy-dy mice and myd mice. The fourth aim will demonstrate the relationship between overexpression of the CT GalNAc transferase and myostatin signaling. Myostatin inhibition is another means of ameliorating muscular dystrophy in mdx mice, and this Aim will identify a novel means of modulating expression of myostatin and its inhibitors by altering muscle glycosylation. The long- term goal of this proposal is to validate the use of the CT GalNAc transferase as a therapeutic in models for DMD and other forms of muscular dystrophy and to develop therapies based on these findings. Another long-term goal is to develop a novel connection between glycosylation and myostatin signaling that may more broadly impact therapies for muscle aging and disease.