Therapy with PPMOs leads to a comprehensive distribution in muscle tissue and efficacy in the mouse model and in cynomolgus macaques: a therapeutic platform for Duchenne muscular dystrophy

Introduction:

Duchenne muscular dystrophy (DMD) is triggered by mutations in the DMD gene. Exon skipping is a therapy strategy at DMD. Appropriately designed morpho-oligomers (PMOs) can cause exon skipping and the formation of an internally truncated dystrophin protein. Approximately 80% of DMD patients have genotypes that are accessible for exon skipping.

Methods:

Therapy of cell-penetrating peptide-conjugated PMOs (PPMOs) with improved muscle penetration was evaluated. Single and repeated doses of PPMOs targeted to mouse exon 23 were administered intravenously (iv) to mdx mice. In addition, primates were repeatedly administered iv doses of PPMOs SRP-5051 against exon 51 and SRP-5053 against exon 53.

Results:

In the mdx mice, PPMO therapy increased exon-23 skipping and dystrophin levels in the quadriceps, diaphragm, and heart. Restoration of dystrophin by PPMOs reduced gene expression of inflammatory and fibrosis markers in muscle and improved muscle function over wild-type and NaCl-treated mdx mice. In cynomolgus monkeys, PPMOs increased exon skipping in all relevant muscle groups studied, including skeletal, cardiac, and smooth muscle.

Conclusion:

These results indicate that PPMOs represent a highly potent therapeutic exon skipping platform for DMD, with long-lasting and reliable therapeutic effects in preclinical models.