G.O.26: Human α7 integrin gene (ITGA7) delivered by adeno-associated virus reverses the phenotype of the double knock out (DKO) mouse devoid of dystrophin and utrophin

Abstract

Duchenne Muscular Dystrophy (DMD) is the most common, severe neuromuscular disorder caused by mutations in the DMD gene. We investigated an alternative to dystrophin replacement by overexpressing ITGA7 using adeno-associated virus (AAV) delivery. ITGA7 is a laminin receptor in skeletal muscle, that like the dystrophin–glycoprotein complex, links the extracellular matrix (ECM) to the internal actin cytoskeleton. ITGA7 is expressed in DMD patients and thus overexpression will not elicit an immune response to the transgene. We delivered rAAVrh.74.MCK.ITGA7 systemically to the more severe mouse model of DMD, the mdx/utrn−/− mouse deficient for both dystrophin and utrophin at 2–4days of age. We demonstrated widespread expression of ITGA7 at the sarcolemma to multiple muscle groups following gene transfer eight weeks post injection. The increased expression of ITGA7 significantly extended longevity and reduced kyphosis and joint contractures, common to the mdx/utrn−/− mouse. The additional <i>α</i>7 expression significantly protected against loss of force following contraction-induced damage and increased specific force in the diaphragm and EDL muscles eight weeks post gene transfer. Taken together, these results show that this therapeutic approach continues to demonstrate promise as a viable treatment for DMD.