Suppressor tRNAs as personalized therapy for nonsense mutation-associated pathologies

Nonsense mutations – associated with many devastating genetic disorders that currently lack effective treatments – prematurely terminate protein synthesis by converting an amino acid-encoding sense codon into a termination codon. Transfer RNAs (tRNAs), essential players in protein synthesis, have naturally evolved to decode sense codons, while avoiding the three stop codons (UGA, UAG, and UAA) that signal termination of translation. Emerging therapeutic strategies increasingly focus on refactoring natural tRNAs into suppressor tRNAs (sup-tRNAs). These engineered sup-tRNAs recognize nonsense mutation-associated premature stop codons (PTCs), restore translation, and recover protein function. This review summarizes recent advances in the design of sup-tRNAs to decode PTCs and discusses critical milestones in developing sup-tRNAs as a personalized therapeutic approach tailored to individual genetic backgrounds for treating pathologic conditions associated with nonsense mutations.