Therapeutic molecules for the development of a read-through approach for diseases caused by nonsense mutations

Nonsense mutations lead to premature translational termination and mRNA destabilization through nonsense-mediated RNA decay. These mutations rise to premature translation termination codons (PTTCs) within the coding region of mRNAs and are the cause of approximately 30% of inherited diseases, including thalassemia and cystic fibrosis. Premature arrest of translation may involve the synthesis of truncated abnormal proteins that can be toxic to target cells through dominant negative or gain-of-function effects. The functional consequences of nonsense mutations are further affected by the nonsense-mediated RNA decay, a cellular mechanism aimed to detect and degrade PTTCs containing mRNAs. In the last few years, it has been demonstrated that drugs (such as aminoglycoside antibiotics) can be designed and produced to suppress premature translation termination, inducing a ribosomal read-through of premature, but not normal termination codons. Moreover, the treatments with aminoglycosides may restore the loss function in patients with nonsense mutations and have introduced new hopes for the development of a pharmacologic approach of these diseases.