Background: Duchenne muscular dystrophy (DMD) is a rare, X-linked neuromuscular disorder caused by mutations in the DMD gene resulting in a lack of functional dystrophin. Antisense phosphorodiamidate morpholino oligomer (PMO)-mediated exon skipping therapies have been approved for several mutations but produce only a very modest amount of dystrophin in skeletal and cardiac muscle, likely due to poor distribution to target tissues and a limited ability to escape the target cell endosome. To overcome these limitations, we designed a family of proprietary cyclic cell-penetrating peptides that form the core of our Endosomal Escape Vehicle (EEV™) technology. This EEV-PMO approach demonstrated exon skipping and dystrophin production in the D2-mdx mouse model of DMD. Furthermore, a single intravenous dose of ENTR-601-44 (a DMD exon 44 splice modulating EEV-PMO) showed durable exon skipping in skeletal and cardiac muscle in human dystrophin-expressing (hDMD) mice and non-human primates for at least 12 weeks post-dose.
Objective: To further address unmet needs in the treatment of DMD, we have developed an EEV-conjugated PMO for the treatment of exon 45 skip amenable DMD.
Results: We show that treatment with this EEV-PMO resulted in exon skipping and dystrophin production in DMD patient-derived skeletal and cardiac muscle cells. Exon skipping was also observed in animal models.
Conclusions: These results demonstrate the therapeutic potential of this EEV-PMO and suggest potential for further study in patients with DMD amenable to exon 45 skipping.