In Vivo Evaluation of Single- and Multi-Exon-Skipping in mdx52 Mice.

Abstract

Exon-skipping therapy is an emerging approach that uses synthetic DNA-like molecules called antisense oligonucleotides (ASOs) to splice out frame-disrupting regions of mRNA, restoring the reading frame, and produce truncated yet functional proteins. Phosphorodiamidate morpholino oligomers (PMOs) are one of the safest among therapeutic ASOs for patients and have recently been approved under the accelerated approval program by the US Food and Drug Administration (FDA) as the first ASO-based drug for Duchenne muscular dystrophy (DMD). Multi-exon-skipping utilizing ASOs can theoretically treat 80-90% of patients with DMD. Here, we describe the systemic delivery of a cocktail of ASOs to skip exon 51 and exons 45 to 55 in the mdx52 mouse, an exon 52 deletion model of DMD produced by gene targeting, and the evaluation of their efficacies in vivo.