Optimization of ACE-tRNAs function in translation for suppression of nonsense mutations

  • Nucleic Acids Res. 2024 Dec 11;52(22):14112-14132. doi: 10.1093/nar/gkae1112.
Joseph J Porter  1 ,  Wooree Ko  1 ,  Emily G Sorensen  1 ,  John D Lueck  1  2  3
Affiliations
  • 1. Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Rochester, NY 14642, USA.
  • 2. Department of Neurology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Rochester, NY 14642, USA.
  • 3. Center for RNA Biology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Rochester, NY 14642, USA.
PMID: 39673265 DOI: 10.1093/nar/gkae1112
Abstract

Nonsense suppressor transfer RNAs (tRNAs) or AntiCodon-Edited tRNAs (ACE-tRNAs) have long been envisioned as a therapeutic approach to overcome genetic diseases resulting from the introduction of premature termination codons (PTCs). The ACE-tRNA approach for the rescue of PTCs has been hampered by ineffective delivery through available modalities for gene therapy. Here we have screened a series of ACE-tRNA expression cassette sequence libraries containing >1800 members in an effort to optimize ACE-tRNA function and provide a roadmap for optimization in the future. By optimizing PTC suppression efficiency of ACE-tRNAs, we have decreased the amount of ACE-tRNA required by ∼16-fold for the most common cystic fibrosis-causing PTCs.

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