Figure 8.

Rationale of combining suppression therapy with NMD inhibition. The presence of a nonsense mutation within an mRNA leads to premature translation termination, resulting in a truncated polypeptide that is nonfunctional and/or unstable. However, nonsense mutations often also trigger nonsense-mediated mRNA decay of the transcript that severely reduces its steady-state levels. The combination of these PTC-induced events contributes to the near complete loss of protein expression that often results in a disease state. Suppression therapy targets premature translation termination by inducing readthrough at PTCs. NMD inhibition could increase the pool of PTC-containing mRNAs available for translation and subsequent PTC suppression. The combination of suppression therapy and NMD inhibition simultaneously targets both PTC-mediated events to enhance protein restoration. [Note: a color version of this figure is available online.]