Advanced antisense oligonucleotide technology for exon skipping in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a common, inherited, incurable, ultimately fatal muscle wasting disease. Antisense oligonucleotide (AO) directed exon skipping restores absent dystrophin protein and trials using phosphorodiamidate morpholino (PMO) AO show encouraging results. However, the benefit of current AO chemistries may be limited by low efficiency systemic dystrophin restoration and little correction in heart. The MDEX Consortium, a world-leading translational medicine group, has developed advanced peptideconjugated PMO (PPMO) technology for enhanced systemic and cardiac PMO delivery and dystrophin correction. We will now identify a lead PPMO compound, optimize its structure, dose route of clinical administration, and evaluate tolerability / efficacy in a Phase I/II dose-escalating, open-label clinical trial in ambulatory patients targeting dystrophin exon 53, in partnership with AVI BioPharma. Advanced PPMO technology shows enhanced systemic and cardiac delivery properties over all AOs currently in clinical trial, without evidence of adverse immunological effects or the production challenges associated with viral delivery systems. Detailed toxicological testing will be required before human studies can commence, but given that efficient targeting of skeletal and cardiac muscle are required for most neuromuscular and cardiac diseases amenable to genetic treatment strategies, advanced PPMO technology is likely to have wide clinical benefit.