Long-term systemic administration of unconjugated morpholino oligomers for therapeutic expression of dystrophin by exon skipping in skeletal muscle: implications for cardiac muscle integrity.

Duchenne muscular dystrophy (DMD) is a lethal X-linked inherited disease caused by mutations in the dystrophin gene and consequent lack of dystrophin in the skeletal, cardiac, and smooth musculature and in the nervous system. Patients die during their mid-twenties because of severe muscle loss and life-threatening respiratory and cardiac complications. The splicing modulation approach mediated by antisense oligonucleotides can restore the production of a partially functional quasi-dystrophin in skeletal muscles. We recently showed that a chronic, 12-month treatment with phosphorodiamidate morpholino oligomers efficiently restored dystrophin in widespread skeletal muscles and led to normal locomotor activity indistinguishable from that of dystrophin-expressing C57 mice. However, no detectable dystrophin expression was observed in the hearts of treated mice. In the present study, histological analyses show a more severe cardiac pathology compared with untreated animals in the face of enhanced locomotor behavior. This observation implies that the increase in locomotor activity of treated mdx mice may have a paradoxical detrimental effect on the dystrophic heart. In the context of skeletal muscle-centric therapies for DMD, our data suggest that particular vigilance should be instigated to monitor emergence of accelerated cardiac dysfunction.