After the selection of several ASO chemistries and the most efficacious ASO sequence designs (Hua et al., 2008), an 18-mer 2′-MOE ASO targeting ISS-N1 emerged as the best performing candidate (Hua et al., 2010; Hua et al., 2011) which demonstrated unprecedented therapeutic efficacy in the restoration of SMN protein levels and greater than 10-fold increase in the lifespan of severe SMA mice (Crawford et al., 2023; Hua et al., 2011). The gene discussed is SMN2; the disease is proximal spinal muscular atrophy.