Differential effects of dystrophin and utrophin gene transfer in immunocompetent muscular dystrophy (mdx) mice

Duchenne muscular dystrophy (DMD) is a fatal disease caused by defects in t he gene encoding dystrophin. Dystrophin is a cytoskeletal protein, which to gether with its associated protein complex, helps to protect the sarcolemma from mechanical stresses associated with muscle contraction. Gene therapy efforts aimed at supplying a normal dystrophin gene to DMD muscles could be hampered by host immune system recognition of dystrophin as a "foreign" pr otein. In contrast, a closely related protein called utrophin is not foreig n to DMD patients and is able to compensate for dystrophin deficiency when overexpressed throughout development in transgenic mice. However, the issue of which of the two candidate molecules is superior for DMD therapy has re mained an open question. In this study, dystrophin and utrophin gene transf er effects on dystrophic muscle function were directly compared in the muri ne (mdx) model of DMD using E1/E3-deleted adenovirus vectors containing eit her a dystrophin (AdV-Dys) or a utrophin (AdV-Utr) transgene. In immunologi cally immature neonatal animals, AdV-Dys and AdV-Utr improved tibialis ante rior muscle histopathology, force-generating capacity, and the ability to r esist injury caused by high-stress contractions to an equivalent degree. By contrast, only AdV-Utr was able to achieve significant improvement in forc e generation and the ability to resist stress-induced injury in the soleus muscle of immunocompetent mature mdx animals. In addition, in mature mdx mi ce, there was significantly greater transgene persistence and reduced infla mmation with utrophin compared to dystrophin gene transfer. We conclude tha t dystrophin and utrophin are largely equivalent in their intrinsic abiliti es to prevent the development of muscle necrosis and weakness when expresse d in neonatal mdx animals with an immature immune system. However, because immunity against dystrophin places an important limitation on the efficacy of dystrophin gene replacement in an immunocompetent mature host, the use o f utrophin as an alternative to dystrophin gene transfer in this setting ap pears to offer a significant therapeutic advantage.