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 <i>DMD</i> 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/<i>mdx</i> mice containing a human exon 52-deleted <i>DMD</i> 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/<i>mdx</i> 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/<i>mdx</i> 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.