Introduction: Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by the expansion of CUG repeats in the 3’-untranslated region of the dystrophia myotonica protein kinase (DMPK) RNA. The expanded CUG repeats form hairpin-loop structures that sequester splicing regulators into toxic nuclear foci, leading to a spliceopathy that drives DM1 clinical manifestations. Naked antisense oligonucleotides (ASO) designed to knockdown (KD) DMPK have shown promise in preclinical models; however, clinical application has failed because of insufficient delivery to muscle upon systemic administration. The FORCETM platform, consisting of an antigen-binding fragment (Fab) that specifically binds transferrin receptor 1 (TfR1), conjugated to a therapeutic oligonucleotide payload, was designed to overcome these limitations.
Methods: DYNE-101, is a Fab-conjugated gapmer ASO that targets human DMPK. hTfR1/DMSXL mice, a novel model expressing human TfR1 and a human DMPK with >1,000 CUG repeats, received 10 mg/kg ASO equivalent of DYNE-101 or vehicle on days 0 and 7. On day 28, DMPK RNA levels and splicing were assessed in the heart and skeletal muscles, while DMPK foci were assessed in the heart. Non-GLP dose-range finding toxicology studies were conducted in non-human primates (NHPs).
Results: hTfR1/DMSXL mice administered with DYNE-101 exhibited a durable 40 to 49% KD of toxic human DMPK RNA, leading to spicing correction in the heart and skeletal muscle. These effects were accompanied by a 49% DMPK foci reduction in the heart. Analysis of gene expression in nuclear and cytoplasmic fractions provided direct evidence that DYNE-101 reduced accumulation of toxic human DMPK RNA trapped in cell nucleus. DYNE-101 was well tolerated in NHPs after repeat dosing.
Conclusion: These data demonstrate that DYNE-101 targets toxic DMPK in the nucleus, thereby driving splicing correction in cardiac and skeletal muscle with a long-lasting effect. DYNE-101 is well-tolerated in NHP, supporting advancement into the clinic.