Prevention of the dystrophic phenotype in dystrophin/utrophin-deficient muscle following adenovirus-mediated transfer of a utrophin minigene

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder caused by the lack of a subsarcolemmal protein, dystrophin. We have previou sly shown that the dystrophin-related protein, utrophin is able to compensa te for the lack of dystrophin in the mdx mouse, the mouse model for DMD. He re, we explore whether utrophin delivered to the limb muscle of dystrophin/ utrophin-deficient double knockout (dko) neonatal mice can protect the musc le from subsequent dystrophic damage. Utrophin delivery may avoid the poten tial problems of an immune response associated with the delivery of dystrop hin to a previously dystrophin-deficient host. Dko muscle (tibialis anterio r) was injected with a first generation recombinant adenovirus containing a utrophin minigene. Up to 95% of the fibres continued expressing the minige ne 30 days after injection. Expression of utrophin caused a marked reductio n from 80% centrally nucleated fibres (CNFs) in the uninjected dko TA to 12 % in the injected dko TA. Within the region of the TA expressing the utroph in minigene, a significant decrease in the prevelance of necrosis was noted These results demonstrate that the utrophin minigene delivered using an ad enoviral vector is able to afford protection to the dystrophin/utrophin-def icient muscle of the dko mouse.