Clinical applications of exon-skipping antisense oligonucleotides in neuromuscular diseases

Abstract

Four exon-skipping antisense oligonucleotides (ASOs) have been approved by the US Food and Drug Administration (FDA) for the treatment of Duchenne muscular dystrophy (DMD), including eteplirsen, golodirsen, viltolarsen, and casimersen. Current data from long-term real-world usage of these ASOs suggests a broad safety profile and a delay in muscle deterioration. Nevertheless, the exon-skipping efficacy and dystrophin protein production of these ASOs are limited, suggesting the need for more efficient ASOs. Over the past decade, many studies have focused on improving ASO efficacy by incorporating novel chemical modifications or bioconjugations of a variety of moieties including peptides or antibodies to increase their cellular uptake by muscle cells, their endosomal escape, and their nuclear import to boost therapeutic efficacy. Many of these newly developed exon-skipping ASOs have been studied in clinical trials in DMD patients, and early findings suggest clear improvements in molecular efficacy compared to the earlier version of ASOs, although the safety track record may not be the same as the first-generation compounds. Here, we summarize the recent preclinical and clinical developments of ASOs and discuss the future challenges of exon-skipping therapies for DMD and other neuromuscular diseases.

Keywords: Duchenne muscular dystrophy; cell-penetrating peptide; clinical trials; endosomal escape; exon skipping; next-generation ASOs; phosphorodiamidate morpholino oligomer; targeted delivery; transferrin receptor antibody.