Figure 4.

Rescuing aberrant splicing with small-molecule drugs. (a) A gene that is normally spliced with three exons is depicted in the top row. The filled circles represent splicing regulators that act at the sites depicted by the filled rectangles to promote splicing. Exons are depicted as outlined boxes. The second row shows the effects of a G-to-A mutation in the downstream intron that creates a binding site (filled rectangle named X) for a regulator (circle Y) which activates a cryptic 5' splice site, leading to the splicing of an additional sequence into the final mRNA and the production of a defective protein. The third row shows the effects of therapy with a drug that abolishes binding of the Y regulator and restores normal splicing. (b) A drug (cylinder) that nonspecifically inhibits both regulator Y and other common regulators will correct the effects of mutation X but will be more toxic than a drug that inhibits only regulator Y.