Commentary: SU9516 increases α7β1 Integrin and Ameliorates Disease Progression in the mdx Mouse Model of Duchenne Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a debilitating X-linked neuromuscular disease with an incidence of 1 in every 5000 boys1. It is caused by mutations in the DMD gene coding for dystrophin, a critical structural protein in muscle. Out-of-frame mutations in the DMD gene, result in the complete loss of dystrophin in muscle fibers2,3 and this leads to a severe disease characterized by progressive muscle deterioration. The functional role of dystrophin is to stabilize the dystrophin glycoprotein complex (DGC), which is composed of sarcolemmal glycoproteins that link the extracellular matrix (ECM) to the actin cystoskeleton in muscle fibers4,5. In the absence of dystrophin, this critical link is lost, rendering the muscle fibers susceptible to damage and contraction-induced injury. Until recently, palliative interventions such as glucocorticoid and corticosteroids were the only options available for disease management in DMD patients. These were accompanied by numerous side effects including weight gain, stunted growth, cataracts and susceptibility to skeletal fractures6,7. In September 2016, the Food and Drug Administration approved a drug for the treatment of patients with amenable mutations in exon 51 of the dystrophin gene. The drug Eteplirsen, a phosphorodiamidate oligonucleotide (PMO), is an exon skipping molecule8 which skips its target exon 51, thereby restoring the dystrophin translational reading frame and enabling expression of a truncated dystrophin molecule in patient muscle fibers. Eteplirsen addresses only 13% of DMD patients because it is mutation-specific9 and a therapeutic that can be universally administered to all DMD patients is still needed.