P.198 Durable AOC mediated exon 44 skipping in non-human primate muscle tissue and dystrophin protein restoration in DMD patient derived skeletal muscle cells

Duchenne muscular dystrophy (DMD) is a neuromuscular disease caused by predominantly out-of-frame mutations in the dystrophin gene. Oligonucleotide-mediated skipping of DMD exons can restore the reading frame and the dystrophin protein expression. Although several oligonucleotides targeting different exons have been approved, their activity is limited due to poor delivery to the muscle. Using our AOCTM technology, we previously demonstrated a robust exon 23 skipping of the dystrophin gene and improved muscle function in mdx mice. AOC 1044 is an investigational drug that affords productive delivery of phosphorodiamidate morpholino oligomers (PMOs) to muscle for treatment of DMD patients amenable to exon 44 skipping, for which there are no approved drugs. Herein, we evaluated activity of AOC 1044 in non-human primates (NHPs) and in DMD patient-derived cells. In NHPs, durable and dose dependent exon 44 skipping was observed using digital droplet PCR (ddPCR) in a broad range of muscle tissue, including the heart, suggesting AOC 1044 is active in vivo at concentrations well above those required for activity (10 – 1000 nM). In patient-derived DMD skeletal muscle cells, PMO44 (the PMO component of AOC 1044), produced concentration-dependent exon 44 skipping and robust restoration of dystrophin protein as well as restoration of the machinery responsible for muscle contraction/relaxation, indicating that the resulting dystrophin was functionally active in human disease cells. These data support the development of AOC 1044 for the treatment of DMD.