P.131 Building a FORCETM platform-based DMD franchise for the treatment of individuals with mutations amenable to exon skipping

Current treatments for Duchenne muscular dystrophy (DMD) use phosphorodiamidate morpholino oligomer (PMO) to induce exon skipping in the dystrophin pre-mRNA, restoring the open reading frame and enabling translation of a shortened but functional dystrophin. Success of this strategy has been hampered by insufficient distribution to muscle. To overcome this limitation, we developed the FORCETM platform, consisting of an antigen-binding fragment (Fab), conjugated to an oligonucleotide payload, which specifically binds the transferrin receptor 1 (TfR1). FORCE-M23D is a mouse-specific Fab-PMO conjugate designed to target TfR1 and skip exon 23 of the murine Dmd transcript to restore dystrophin expression in the mdx mouse model of DMD. We demonstrated that a single dose of FORCE-M23D substantially enhanced PMO delivery to cardiac and skeletal muscles in mdx mice, compared to the unconjugated PMO payload. Accordingly, FORCE-M23D led to robust and durable exon skipping and dystrophin restoration, and improved functional outcomes, compared to the unconjugated PMO. Additionally, Dyne's clinical candidate, DYNE-251, a Fab-conjugated PMO designed to skip DMD exon 51, was evaluated in non-human primates (NHPs). Five weekly doses of DYNE-251 resulted in pronounced exon 51 skipping in the heart, diaphragm, and quadriceps 8 weeks after the first dose. A 13-week GLP toxicology study of DYNE-251 in NHPs demonstrated a favorable safety profile. Lastly, we have begun development of FORCE conjugates for the treatment of exon 53 and exon 45 skipping amenable patients. A novel DMD exon 53 skipping conjugate achieved robust and dose-dependent skipping and dystrophin restoration in DMD patient myotubes. This conjugate resulted in superior skipping of exon 53 compared to unconjugated PMO. Collectively, these data support utilizing the FORCE platform for the development of therapies for individuals with DMD mutations amenable to exon skipping.