rAAVrh74.MCK.GALGT2 Protects against Loss of Hemodynamic Function in the Aging mdx Mouse Heart.

Dilated cardiomyopathy is a common cause of death in patients with Duchenne muscular dystrophy (DMD). Gene therapies for DMD must, therefore, have a therapeutic impact in cardiac as well as skeletal muscles. Our previous studies have shown that GALGT2 overexpression in mdx skeletal muscles can prevent muscle damage. Here we have tested whether rAAVrh74.MCK.GALGT2 gene therapy in mdx cardiac muscle can prevent the loss of heart function. Treatment of mdx hearts with rAAVrh74.MCK.GALGT2 1 day after birth did not negatively alter hemodynamic function, tested at 3 months of age, and it prevented early left ventricular remodeling and expression of fibrotic gene markers. Intravenous treatment of mdx mice with rAAVrh74.MCK.GALGT2 at 2 months of age significantly improved stroke volume and cardiac output compared to mock-treated mice analyzed at 17 months, both at rest and after stimulation with dobutamine. rAAVrh74.MCK.GALGT2 treatment of mdx heart correlated with increased glycosylation of α-dystroglycan with the CT glycan and increased utrophin protein expression. These data provide the first demonstration that GALGT2 overexpression can inhibit the loss of cardiac function in the dystrophin-deficient heart and, thus, may benefit both cardiac and skeletal muscles in DMD patients.