Exon Skipping and Dystrophin Production with a Novel EEV-Conjugated, Exon 45 Skip Amenable PMO in Preclinical Models of DMD


Pre-Clinical Research

Poster Number: 239


Nelsa Estrella, Entrada Therapeutics, Amy Hicks, PhD, Entrada Therapeutics, Ajay Kumar, Phd., Entrada Therapeutics, Christopher Brennan, Entrada Therapeutics, Xiang Li, Entrada Therapeutics, Anushree Pathak, Entrada Therapeutics, Mahboubeh Kheirabadi, Entrada Therapeutics, Patrick Dougherty, Entrada Therapeutics, Wenlong Lian, Entrada Therapeutics, Nanjun Liu, Entrada Therapeutics, Ningguo Gao, Entrada Therapeutics, Daniel Wang, Entrada Therapeutics, Matthew Streeter, Entrada Therapeutics, Mohanraj Dhanabal, Entrada Therapeutics, Ziqing Leo Qian, Entrada Therapeutics, Natarajan Sethuraman, Entrada Therapeutics, Mahasweta Girgenrath, PhD, Entrada Therapeutics

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.