Antisense oligonucleotide (AO)-mediated exon-skipping
therapeutics shows great promise for
Duchenne muscular dystrophy (DMD) patients. However, recent failure with
drisapersen, an AO candidate
drug in phase 3 trial, highlights the importance of exploring other effective AO chemistries for DMD. Previously, we demonstrated the appreciable
biological activity of
peptide nucleic acid (PNA) AOs in restoring
dystrophin expression in
dystrophin-deficient mdx mice intramuscularly. Here, we further explore the systemic potential and feasibility of PNA AOs in mediating exon skipping in mdx mice as a comprehensive systemic evaluation remains lacking. Systemic delivery of PNA AOs resulted in therapeutic level of
dystrophin expression in body-wide peripheral muscles and improved dystrophic pathology in mdx mice without any detectable toxicity. Up to 40% of
dystrophin restoration was achieved in gastrocnemius, to a less extent with other skeletal muscles, with no
dystrophin in heart. Notably, comparable systemic activity was obtained between PNA AOs and
phosphorodiamidate morpholino oligomer, a DMD AO chemistry in phase 3 clinical trial, under an identical dosing regimen. Overall, our data demonstrate that PNA is viable for DMD exon-skipping
therapeutics with 20 mer showing the best combination of activity, solubility, and safety and further modifications to increase PNA aqueous solubility can enable longer, more effective
therapeutics without the associated toxicity.