Given current challenges in gene-replacement and gene-editing therapies, tRNA-based approaches show promise for treating diseases caused by nonsense mutations. We engineered a suppressor tRNA gene for AAV delivery in vivo that targets UGA — the stop codon that is most commonly introduced by pathogenic nonsense mutations — in a disease-agnostic manner.
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References
Wang, J. et al. AAV-delivered suppressor tRNA overcomes a nonsense mutation in mice. Nature 604, 343–348 (2021). This paper reports that UAG-sup-tRNA delivered by rAAV rescues the disease-associated PTC in multiple tissues in a mouse model of Hurler syndrome.
Albers, S. et al. Engineered tRNAs suppress nonsense mutations in cells and in vivo. Nature 618, 842–848 (2023). This paper reports that an in vitro transcribed UGA-sup-tRNA delivered via LNPs in mice mediates efficient readthrough of the PTC in a co-delivered reporter mRNA.
Pierce, S. E. et al. Prime editing-installed suppressor tRNAs for disease-agnostic genome editing. Nature https://doi.org/10.1038/s41586-025-09732-2 (2025). This paper uses prime editing to convert an endogenous tRNA into a UAG-sup-tRNA and rescues disease pathology in a mouse model of Hurler syndrome.
Mullick, A. et al. The cumate gene-switch: a system for regulated expression in mammalian cells. BMC Biotechnol. 6, 43 (2006). This paper uses the bacterial operator–repressor CymR/CuO system to control gene expression in mammalian cells.
Porter, J. J. et al. Optimization of ACE-tRNAs function in translation for suppression of nonsense mutations. Nucleic Acids Res. 52, 14112–14132 (2024). This paper optimizes the flanking and body sequences of sup-tRNA to improve PTC suppression efficiency in vitro.
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This is a summary of: Xu, M. et al. An engineered UGA suppressor tRNA gene for disease-agnostic AAV delivery. Nat. Biotechnol. https://doi.org/10.1038/s41587-025-02982-5 (2026).
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AAV-delivered UGA suppressor tRNA for disease-agnostic in vivo gene therapy. Nat Biotechnol (2026). https://doi.org/10.1038/s41587-026-02999-4
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DOI: https://doi.org/10.1038/s41587-026-02999-4
