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

摘要

Nonsense mutations lead to premature translational termination and mRNA destabilization through non-sense-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 ab-normal proteins that can be toxic to target cells throu-gh dominant negative or gain-of-function effects. The functional consequences of nonsense mutations are further affected by the nonsense-mediated RNA de-cay, a cellular mechanism aimed to detect and degrade PTTCs containing mRNAs. In the last few years, it has been demonstrated that drugs (such as aminoglycosi-de antibiotics) can be designed and produced to sup-press 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 pa-tients with nonsense mutations and have introduced new hopes for the development of a pharmacologic approach of these diseases.