Figure 2. ASO-mediated SMN2 splicing correction as a therapy for SMA.

(A) Diagrammatic representation of splicing cis-elements in SMN2 intron 7. Numbering begins from the first position of intron 7. The negative cis-element ISS-N1 (yellow box) contains two hnRNP A1 binding sites (magenta boxes) and has emerged as a leading ASO target for splicing correction in SMA. Green ovals represent TIA-1 binding sites, an enhancer of exon 7 splicing. (B) Representative ISS-N1-targeting ASOs tested in SMA mouse models. Intron 7 sequence is in lower caps and ASO sequences are in upper caps. The chemistry for each ASO is listed to the left of the sequence. The outcomes for studies in which the ASOs were tested are listed to the right of the sequence; references are denoted in brackets. Abbreviations: ASO, antisense oligonucleotide; ISS-N1, intronic splicing silencer N1; hnRNP A1, heterogenous ribonucleoprotein A1; TIA1, T-cell restricted intracellular antigen 1; LDI, long-distance interaction; 2′-OMe, an ASO with phosphorothioate backbone and 2′-O-methyl modification; MOE, an ASO with phosphorothioate backbone and 2′-O-methoxyethyl modification; MO, morpholino; GM, SMA patient fibroblast cells (cell line GM03813); TW, Taiwanese SMA mouse model; Δ7, Δ7 SMA mouse model.