1. ¹Department of Neurology, University of Washington, Seattle, Washington, USA
2. ²Department of Medicine, University of Washington, Seattle, Washington, USA
3. ³Department of Biochemistry, University of Washington, Seattle, Washington, USA

Correspondence: Jeffrey S. Chamberlain, Department of Neurology, University of Washington School of Medicine, Health Sciences Building room K233, 1959 NE Pacific Street, Seattle, Washington 98195-7720, USA. E-mail: jsc5@washington.edu

Received 4 October 2007; Accepted 21 January 2008; Published online 4 March 2008.

Abstract

Restoring dystrophin expression in the muscles of patients with Duchenne muscular dystrophy (DMD) may halt or reverse the degenerative wasting and weakness that causes premature death. However, the therapeutic efficacy of an intervention may be limited by the extent of disease progression prior to treatment. In this study, we considered the potential for ameliorating the pathology in a mouse model of advanced-stage muscular dystrophy by systemic administration of recombinant adeno-associated viral (rAAV6) vectors encoding a microdystrophin expression construct. The treatment of 20-month-old mdx mice restored body-wide expression of a dystrophin-based protein in striated musculature. In aged mice that received treatment, the resultant dystrophin expression was associated with improved hindlimb and respiratory muscle morphology and function, concomitant with reduced muscle fiber degeneration. The findings demonstrate that an established dystrophic state remains amenable to improvement with appropriate intervention and, by some measures, may even achieve benefits similar to those observed with intervention early in disease progression. The capacity to ameliorate the pathology in an animal model of advanced-stage muscular dystrophy suggests that interventions ultimately proven to exert a therapeutic effect in young patients may offer benefits to older patients or those with advanced conditions of progressive muscular dystrophy.