Antisense phosphorodiamidate morpholino oligomer (PMO)-mediated exon skipping therapies for Duchenne muscular dystrophy (DMD) produce only a very modest amount of dystrophin in skeletal muscle. To enhance PMO delivery to target tissues, we designed a family of proprietary cyclic cell-penetrating peptides that form the core of the Endosomal Escape Vehicle (EEV™) platform. The therapeutic potential of EEV-PMO constructs for the treatment of DMD was confirmed in several preclinical studies using the D2-mdx mouse model. EEV-PMO-23 (EEV-exon 23 skipping PMO construct) demonstrated robust exon skipping and dystrophin production in both skeletal and cardiac muscle and improved skeletal muscle contractile force to wild type levels.
To further examine the therapeutic potential of this approach, the efficacy of exon 44 and 45 skip amenable EEV-PMO conjugates was assessed. ENTR-601-44 (EEV-exon 44 skipping PMO construct) showed durable exon skipping in skeletal and cardiac muscle in non-human primates for at least 12 weeks following a single IV dose. Additionally, ENTR-601-45 (EEV-exon 45 skipping PMO construct) produced robust exon skipping and dystrophin production in skeletal and cardiac muscle cells derived from patients with exon 45 skip amenable DMD.
These results demonstrate the ability of the EEV platform to efficiently deliver exon skipping oligonucleotides to skeletal and cardiac muscle in preclinical models of DMD and support the potential for further study in patients with DMD. The first-in-human, phase 1 clinical trial of ENTR-601-44 in healthy human subjects is ongoing in the United Kingdom with an estimated completion date in the second half of 2024.