Antisense therapy with both chemistries of phosphorodiamidate morpholino 
oligomers (PMOs) and 2'-O-methyl phosphorothioate has demonstrated the 
capability to induce dystrophin expression in Duchenne muscular dystrophy (DMD) 
patients in phase II-III clinical trials with benefit in muscle functions. 
However, potential of the therapy for DMD at different stages of the disease 
progression is not understood. In this study, we examined the effect of 
peptide-conjugated PMO (PPMO)-mediated exon skipping on disease progression of 
utrophin-dystrophin-deficient mice (dko) of four age groups (21-29, 30-39, 40-49 
and 50+ days), representing diseases from early stage to advanced stage with 
severe kyphosis. Biweekly intravenous (i.v.) administration of the PPMO restored 
the dystrophin expression in nearly 100% skeletal muscle fibers in all age 
groups. This was associated with the restoration of dystrophin-associated 
proteins including functional glycosylated dystroglycan and neuronal nitric 
synthase. However, therapeutic outcomes clearly depended on severity of the 
disease at the time the treatment started. The PPMO treatment alleviated the 
disease pathology and significantly prolonged the life span of the mice 
receiving treatment at younger age with mild phenotype. However, restoration of 
high levels of dystrophin expression failed to prevent disease progression to 
the mice receiving treatment when disease was already at advanced stage. The 
results could be critical for design of clinical trials with antisense therapy 
to DMD.