Enhanced antisense oligonucleotide delivery reveals that transcript turnover impacts apparent splicing rescue in myotonic dystrophy

However, rationale for biomarker selection remains a topic of debate. Here, we show that a cyclic cell-penetrating peptide that escapes endosomes enhances muscle delivery of a phosphorodiamidate morpholino oligonucleotide (PMO) designed to block pathogenic CUG repeat expansions in HSALR mice.

A single systemic administration rescued mis-splicing and eliminated myotonia one-week post-injection, with partial splicing rescue evident after 24 hours. Interestingly, some exons showed more robust rescue than others, but relationships between MBNL concentration ([MBNL]) and Percent Spliced In (Ψ) could not fully explain extent of rescue. We hypothesized that since pre-existing transcripts must be degraded to reveal full drug effect, rates of transcript replacement might account for these discrepancies.