433P Therapeutic potential of ENTR-601-44, an Endosomal Escape Vehicle (EEV™) - Oligonucleotide Conjugate for the treatment of exon 44 skip amenable DMD

Currently approved 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 c...

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Published in:Neuromuscular disorders : NMD 2024-10, Vol.43, p.104441, Article 104441.304
Main Authors: Oldham, M., Estrella, N., Kumar, A., Hicks, A., Brennan, C., Blake, S., Li, X., Pathak, A., Kheirabadi, M., Dougherty, P., Lian, W., Liu, N., Gao, N., Streeter, M., Stadheim, A., Dhanabal, M., Qian, Z., Girgenrath, M., Sethuraman, N.
Format: Article
Language:English
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Summary:Currently approved 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. Studies in D2-mdx mice demonstrated that EEV-PMO-23 (an EEV-exon 23 skipping PMO construct) dosed every four or six weeks produce dystrophin in skeletal and cardiac muscle. Based on these findings, we examined the therapeutic potential of a DMD exon 44 skipping EEV-PMO construct (ENTR-601-44) in cell and animal models. ENTR-601-44 produced robust exon skipping and restoration of dystrophin protein expression in DMD patient-derived skeletal muscle cells harboring an exon 44 amenable mutation. In addition, single IV doses of ENTR-601-44 led to dose-dependent exon skipping in cardiac and skeletal muscle in human dystrophin-expressing (hDMD) mice and demonstrated robust exon skipping in cardiac and skeletal muscle of nonhuman primates. Together, these findings suggest therapeutic potential of ENTR-601-44 in preclinical models and support further study in patients with DMD amenable to exon 44 skipping. The first-in-human, phase 1 clinical trial of ENTR-601-44 in healthy human subjects is ongoing in the UK with an estimated completion date in the second half of 2024.
ISSN:0960-8966
DOI:10.1016/j.nmd.2024.07.313