Emerging studies suggest that in Duchenne muscular dystrophy (DMD), the lack of dystrophin leads to changes in phenotype and function of satellite cells, resulting in altered gene expression, metabolism, increased inflammation and oxidative stress, and a greater likelihood of cell senescence. This exacerbates disease progression by impairing muscle maintenance and regeneration. Notably, targeted correction of satellite cell dysfunction in DMD has been shown to ameliorate pathophysiology in preclinical models.
Despite notable advancements in therapeutic strategies for DMD such as antisense exon skipping oligonucleotides and gene therapies, these treatments primarily target dystrophic myofibers and show only modest efficacy. Furthermore, approved oligonucleotide therapeutics encounter challenges such as poor cellular uptake and limited endosomal escape, which may necessitate higher therapeutic dosages.
To address these issues, we developed the Endosomal Escape Vehicle (EEV™) family of cyclic cell-penetrating peptides. This platform has effectively facilitated the delivery of exon-skipping phosphorodiamidate morpholino oligomers (PMOs) to skeletal and cardiac muscle. In experiments with the D2-mdx mouse model of DMD, we demonstrated significant exon skipping and dystrophin production in both cardiac and skeletal muscles, leading to improved muscle function that persisted for at least 12 weeks following the final dose. Moreover, we observed that PMOs were successfully delivered to satellite cells and were found to colocalize in the nuclei of newly regenerated fibers in muscle tissue three months post dosing. These data suggest that the successful delivery of exon-skipping PMOs to the satellite cell compartment plays a significant role in the sustained effects observed with EEV therapeutics, potentially leading to a more comprehensive improvement in DMD pathophysiology.