A large number of disease-causing variants create a premature stop codon (PTC). This typically leads to degradation of the mutant mRNA by nonsense-mediated decay (NMD) or production of nonfunctional truncated proteins. An increasing number of recent studies have demonstrated that aminoglycosides or a new less toxic drug, ataluren (PTC124), may lead to read-through of PTCs. This may be used therapeutically and there are already a few ongoing clinical trials. However, the number of diseases where these drugs have been characterized thoroughly in patient cells is limited and results are not uniform.
In this issue, Sanchez-Alucida et al. (Hum Mutat 33:973–980, 2012) investigate the effect of three such drugs, including ataluren, on a number of PTC mutations that cause the severe metabolic disease propionic acidemia (PA). The authors first use in vitro transcription/translation and transfection experiments to test the ability of the drugs to induce read-through of different PTCs and to establish whether the resulting variant proteins are functional. Then, they demonstrate a significant therapeutic potential for some mutations, since they can restore enzyme activity in patient cells to levels that are known to be sufficient to change PA disease phenotype. This result may hold true also with many other inherited enzyme defects, where even modest increases in residual enzyme activity could dramatically change disease course.
A major strength in the study is that the authors investigate several of the determinative factors simultaneously. Consistent with other studies, they show that UGA codons have the most efficient read-through and that there are differences in the response of different PTCs to different drugs - indicating that there appears not to be a single wonder drug for all PTCs. They also show that the amounts of PTC-containing mRNA in patient cells is crucial. The functionality of the proteins generated by drug-induced read-through is also critical. The present study convincingly shows that there is reason to hope that patients with PTC mutations, which fulfill the above criteria, can be treated successfully in the future.