Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder that is the leading genetic cause of infantile death, occurring in ~1:10,000 live births. We have identified “Element 1” (E1) as a potent repressor of SMN2 exon 7 inclusion. Previously, we identified and characterized a lead candidate antisense oligonucleotide (ASO) that significantly extended survival of two important SMA animal models of disease. Presented are results from experiments that demonstrate the effect of various ASO candidates and their effect on animal survival and production of SMN protein. Additionally, we present data on the optimization of this approach and identification of a lead pharmaceutical candidate E1v1.11, which has been well characterized in animal models for safety and efficacy. We have compared these results to published results of Spinraza in the same animal model (and similar dosing regimen) and show a 12x-fold improvement in animal survival and a 150x fold increase in maximum tolerated dose.