FORCETM platform delivers exon skipping PMO, leads to durable increases in dystrophin protein in mdx mice and is well tolerated in NHPs


Pre-Clinical Research

Poster Number: 139


Cody Desjardins, PhD, Dyne Therapeutics, Reshmii Venkatesan, Dyne Therapeutics, Emma O'Donnell, Dyne Therapeutics, John Hall, Dyne Therapeutics, Ryan Russo, Dyne Therapeutics, Sean Spring, Dyne Therapeutics, Kim Tang, Dyne Therapeutics, John Davis, Dyne Therapeutics, Timothy Weeden, Dyne Therapeutics, Stefano Zanotti, Dyne Therapeutics, Oxana Beskrovnaya, Dyne Therapeutics

Purpose: Approved therapies for Duchenne muscular dystrophy (DMD) use phosphorodiamidate morpholino oligomer (PMO) to induce exon skipping in the dystrophin pre-mRNA thereby restoring the open reading frame and enabling translation of a shortened but functional dystrophin protein. However, success of this strategy has been hampered by insufficient distribution of PMO to cardiac and skeletal muscle. To overcome these limitations, we developed the FORCETM platform, consisting of an antigen-binding fragment (Fab) that specifically recognizes the transferrin receptor 1, conjugated to an oligonucleotide payload.

Methods: FORCE-M23D is a Fab-conjugated PMO designed to skip exon 23. Mdx mice, a model of DMD, were administered FORCE-M23D containing the equivalent of 10 or 30 mg/kg PMO. Muscle PMO concentration, exon skipping, dystrophin protein, and functional outcomes were measured at multiple timepoints. Dyne’s clinical candidate, DYNE-251, was evaluated for its ability to induce exon 51 skipping in non-human primates (NHPs). The safety profile of DYNE-251 was assessed in a GLP toxicity study in NHPs.

Results: A single dose of FORCE-M23D achieved dose-dependent, robust, and durable exon skipping and dystrophin restoration in muscle of mdx mice. At 4 weeks, 30 mg/kg of FORCE-M23D led to dystrophin restoration of 77%, 90%, and 51% of wild-type by Western blot in the heart, diaphragm, and quadriceps, respectively, with 68% dystrophin-positive fibers in quadriceps and near-complete restoration of sarcolemmal dystrophin localization in heart and diaphragm. FORCE-M23D treatment also led to improved function in mdx mice.

In NHPs, 5 weekly 30 mg/kg doses of DYNE-251 resulted in 43%, 52%, and 18% exon 51 skipping in the heart, diaphragm, and quadriceps, respectively, 8 weeks after the first dose. DYNE-251 was well tolerated in the GLP toxicity study in NHP.

Conclusions: Our results suggest that the FORCE platform may provide a promising approach to addressing DMD, and support advancement of DYNE-251 to the clinic.