2. Academic Validation
  3. ACE-tRNAs are a platform technology for suppressing nonsense mutations that cause cystic fibrosis

ACE-tRNAs are a platform technology for suppressing nonsense mutations that cause cystic fibrosis

  • Nucleic Acids Res. 2025 Jul 8;53(13):gkaf675. doi: 10.1093/nar/gkaf675.
Wooree Ko 1,  Joseph J Porter 1,  Sacha Spelier 2 3,  Emily G Sorensen 1,  Priyanka Bhatt 4,  Jeffrey T Gabell 5,  Isabelle van der Windt 2 3,  Tyler Couch 1,  Kevin Coote 4,  Martin Mense 4,  Jeffrey M Beekman 2 3 6,  John D Lueck 1 7 8
Affiliations

Affiliations

  • 1 Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, United States.
  • 2 Department of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, University Medical Center, Utrecht University, 3584 EA, Utrecht, The Netherlands.
  • 3 Regenerative Medicine Utrecht, University Medical Center, Utrecht University, 3584 CT, Utrecht, The Netherlands.
  • 4 Cystic Fibrosis Foundation Therapeutics Lab, Cystic Fibrosis Foundation, Lexington, MA 02421, United States.
  • 5 Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, United States.
  • 6 Centre for Living Technologies, Alliance Eindhoven University of Technology, Wageningen University and Research, Utrecht University, University Medical Center Utrecht, Utrecht 3584 CB, The Netherlands.
  • 7 Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, United States.
  • 8 Center for RNA Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, United States.
PMID: 40650978 DOI: 10.1093/nar/gkaf675
Abstract

Nonsense mutations arise from single nucleotide substitutions that result in premature termination codons (PTCs). PTCs result in little to no full-length protein production and decreased mRNA stability due to the nonsense-mediated mRNA decay (NMD) pathway. We provide evidence that anticodon-edited (ACE-) tRNAs efficiently suppress the most prevalent cystic fibrosis (CF)-causing PTCs, promoting significant rescue of endogenous cystic fibrosis transmembrane conductance regulator (CFTR) transcript abundance and channel function in different model systems. We show that our best-performing ACE-tRNA, which decodes all UGA PTCs to a leucine amino acid, markedly rescues CFTR function from the most prevalent CF-causing PTCs, all of which arose from nonleucine encoding codons. Using this single ACE-tRNA variant, we demonstrate significant rescue of CFTR function in an immortalized airway cell line and two different primary CF patient-derived intestinal cell models with CFTR nonsense mutations. Further, we demonstrate that leucine substitution CFTR variants are highly functional. Thus, ACE-tRNAs have promise as a platform therapeutic for CF and Other nonsense-associated diseases.

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