Duchenne muscular dystrophy (DMD) is a fatal disease caused by defects in the gene encoding
dystrophin.
Dystrophin is a cytoskeletal
protein, which together 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"
protein. In contrast, a closely related
protein called
utrophin is not foreign 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 remained an open question. In this study,
dystrophin and
utrophin gene transfer effects on dystrophic muscle function were directly compared in the murine (mdx) model of DMD using E1/E3-deleted adenovirus vectors containing either a
dystrophin (AdV-Dys) or a
utrophin (AdV-Utr) transgene. In immunologically immature neonatal animals, AdV-Dys and AdV-Utr improved tibialis anterior muscle histopathology, force-generating capacity, and the ability to resist injury caused by high-stress contractions to an equivalent degree. By contrast, only AdV-Utr was able to achieve significant improvement in force generation and the ability to resist stress-induced injury in the soleus muscle of immunocompetent mature mdx animals. In addition, in mature mdx mice, there was significantly greater transgene persistence and reduced
inflammation with
utrophin compared to
dystrophin gene transfer. We conclude that
dystrophin and
utrophin are largely equivalent in their intrinsic abilities to prevent the development of muscle
necrosis and weakness when expressed 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 of
utrophin as an alternative to
dystrophin gene transfer in this setting appears to offer a significant therapeutic advantage.