M.I.4 Progress in gene therapy for muscular dystrophy using vascular delivery of GALGT2

Abstract

The myomatrix present at the neuromuscular junction, as well as the transmembrane receptor complexes linking it to the F-actin cytoskeleton, are distinct from those present along the rest of the skeletal myofiber sarcolemmal membrane. Covalent protein modifications, including glycosylation, also differ between these two muscle regions. We have shown that overexpression of GALGT2, a glycosyltransferase normally confined to the neuromuscular synapse, in mouse or macaque skeletal muscle leads to ectopic glycosylation of alpha dystroglycan and the overexpression of normally synaptic dystroglycan-binding proteins, including utrophin, laminin alpha5 and agrin. As a likely result of these and related changes, GALGT2 overexpression can inhibit the development of muscle disease in the mdx model of Duchenne muscular dystrophy, the dyW model of Congenital Muscular Dystrophy 1A, and the Sgca−/− model of Limb Girdle Muscular Dystrophy 2D. In addition, GALGT2 overexpression can increase binding of myomatrix proteins to alpha dystroglycan and prevent muscle damage induced by eccentric contractions. Moreover, elimination of endogenous GALGT2 upregulation in mdx muscles leads to more severe disease. These proof of concept studies suggest that GALGT2 is a surrogate gene therapy with potentially broad applications in muscle disease. With help from a team of investigators in the Center for Gene Therapy at Nationwide Children's Hospital, we are developing methods for vascular delivery of gene therapies, using both gene replacement and surrogate gene strategies, with the goal of performing clinical trials in multiple forms of muscular dystrophy. This work was supported by grants from the NIH U54 NS055958 and R01 AR060949.