O.12 Peptide-enhanced uptake and bioactivity of antisense oligonucleotides in muscle and heart of DMD and DM1 mouse models

Abstract

RNA-modulation by antisense oligonucleotides (AONs) represents an interesting therapeutic approach for different neuromuscular disorders, such as Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1). DMD is caused by out of frame mutations in the DMD gene. AON-mediated exon skipping, aimed to restore the disrupted reading frame of the dystrophin transcript, is currently in (pre-) clinical development. In DM1, DM protein kinase transcripts contain a toxic expanded (CUG) n repeat stretch. Suppression of these toxic transcripts by AONs is currently being explored as a potential molecular intervention for DM1. For both diseases, efficient body-wide delivery of the AONs to muscle tissue and heart would enhance their therapeutic effect. The lack of dystrophin in DMD muscle results in more permeable muscle fibers, which, in the mdx mouse model, was demonstrated to promote AON uptake in muscle but to a lesser extent in heart. As the muscle fiber membranes are not impaired in DM1, various delivery-enhancing complexes and ligands are being explored to obtain sufficient muscle and heart uptake of AONs. Here, we present results with a 7-amino acid linear peptide that, conjugated to 2’-O-methyl phosphorothioate AONs, seems to enhance their uptake and bioactivity in muscle and, particularly, heart, in both DMD and DM1 mouse models.