An octaguanidine–morpholino oligo conjugate improves muscle function of mdx mice

INTRODUCTION: Skeletal muscles of mdx mice lack functional levels of dystrophin due to a mutation in Dmd exon 23. Morpholino antisense oligomers can induce expression of a truncated dystrophin by redirecting splicing to skip processing of exon 23. METHODS: We tested whether systemic administration of Vivo-Morpholino, an octaguanidine delivery moiety-Morpholino conjugate that targets exon 23 (VMO23), restored function to muscles of mdx mice. RESULTS: Extensor digitorum longus (EDL) muscles of mdx mice were weaker, less powerful, and showed greater functional deficits after eccentric contractions than normal. VMO23 treatment normalized EDL force and power of mdx mice and eliminated their exaggerated sensitivity to eccentric contractions. Diaphragm muscle strips from mdx mice also produced lower-than-normal force and power, and these variables were restored to normal, or near-normal, levels by VMO23 treatment. CONCLUSION: These results provide a functional basis for continuing development of VMO23 as a treatment for Duchenne muscular dystrophy.