Exon skipping with antisense oligonucleotides (ASO) offers a powerful strategy to restore functional dystrophin protein in a subset of patients with Duchenne muscular dystrophy. First-generation exon skippers can trigger exon skipping, but the resulting protein levels are often too low to meaningfully impact patient outcomes. To overcome this, we performed comprehensive tiling of exon 51 to pinpoint the most effective target sites. We then screened various ASO sequences and chemistries to find the most effective candidates. Our efforts led to the discovery of BMN 351, an ASO that targets a novel site in exon 51 and includes chemical modifications that boost its stability, tissue distribution, and cellular uptake. In humanized DMD mice with the DMDdel52 mutation, BMN 351 generated high levels of exon skipping (~50% skipping in heart, diaphragm, and quadriceps via ddPCR). It also restored expression of near full-length dystrophin (~30-50% in heart and quadriceps), which rescued muscle pathology and gait deficit. In non-human primates (NHP), BMN 351 delivered strong exon skipping activity (~10-25% in bicep, heart, and quadriceps via ddPCR). BMN 351 is currently being studied in an on-ongoing Ph1/2 trial (NCT06280209) and stands out as a highly promising new therapy for patients with Exon 51 skip-amenable mutations.