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. 2014 Dec 1;2(1):e970955. doi: 10.4161/23723548.2014.970955

Figure 1.

Figure 1.

Splicing-based therapeutic approaches. The diagram shows a cassette exon splicing event. Three exons (rectangles) and 2 introns (black lines) are shown. The black box in the middle exon represents an exonic splicing enhancer (ESE) sequence that is recognized by the enhancer splicing factor (black SF). The orange box in the middle exon represents an exonic splicing silencer (ESS) sequence that is recognized by the splicing factor silencer (orange SF). SF3B binds to the branch point sequence (BPS) in the intron. (A) No treatment. In this scenario 2 mRNAs can be generated: one in which the middle exon is included in the mRNA (mRNA A) and a second in which the middle exon is skipped (mRNA B). The width of the black arrows indicates that formation of mRNA A is favored. (B) SF3B inhibitor (SSA) prevents binding of SF3B to the BPS, resulting in inhibition of splicing. In this case the intronic sequences are retained in the mRNA and may contain a premature stop codon. This mRNA will be recognized by the NMD machinery and degraded. Alternatively, the premature stop codon will not lead to degradation of the mRNA, but rather to the production of a truncated protein. Another outcome is that the transcript will be retained in the nucleus. SF3B inhibitors act as general inhibitors of splicing and do not target a specific mRNA. (C) Inhibition of specific splicing factors. Small molecules that block activity (e.g., phosphorylation) of a specific SF (in this example a SF that binds to the ESE) will prevent its binding to the cis elements in the pre-mRNA and result in reduced inclusion of the exon. Other silencer SFs will still bind to the pre-mRNA to favor skipping of this exon. As a result, more mRNA B will be generated. (D) ASOs/siRNAs directed against the SF mRNA will lead to degradation of the SF mRNA, and in this case to decreased binding to the ESE resulting in decreased inclusion of the middle exon. Other SFs can still bind to the pre-mRNA and favor skipping and production of mRNA B. (E) Specific ASOs designed to prevent binding of the SF to the cis elements in the mRNA (ESE) will lead to decreased inclusion of the middle exon. Other SFs can still bind to the pre-mRNA and favor production of mRNA B. (F) Specific ASOs designed to prevent binding of the splicing machinery result in skipping of the exon and production of more mRNA B.