BMN 351-Induced Exon Skipping and Dystrophin Expression in Skeletal and Cardiac Muscle Lead to Preservation of Motor Function in a Mouse Model of Exon 51 Skip-Amenable Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is caused by mutations of the DMD gene that prevent the expression of functional dystrophin protein. BMN 351 is an antisense oligonucleotide (ASO) designed to induce skipping of exon 51 of dystrophin pre-mRNA and production of internally deleted but functional dystrophin. We determined whether extended-term BMN 351 dosing leads to exon skipping, dystrophin production, and improved motor function in hDMDdel52/mdx mice containing a human exon 52-deleted DMD transgene. Weekly intravenous doses of vehicle, 6 mg/kg BMN 351, or 18 mg/kg BMN 351 were administered for 25 weeks, and samples were analyzed 4 and 12 weeks post-dosing. BMN 351 produced dose-dependent exon skipping levels in the heart and quadriceps muscles, accompanied by dose-dependent increases in mean dystrophin levels of 17% to 55% 12 weeks post-dosing. Compared with vehicle-treated hDMDdel52/mdx mice, BMN 351 ameliorated DMD-related histopathologic changes in the gastrocnemius muscle and heart. Both BMN 351 doses preserved fine motor kinematics, which was worse in vehicle-treated hDMDdel52/mdx mice compared with wild-type 4 and 12 weeks post-dosing. Liver samples demonstrated findings consistent with ASO accumulation, to which mice are considered especially sensitive compared to humans and other non-clinical species. These results support further non-clinical and clinical development of BMN 351.