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<p>Suppressor transfer RNAs (sup-tRNAs) have the potential to rescue nonsense mutations in a disease-agnostic manner and are an alternative therapeutic approach for many rare and ultrarare disorders. Among all human pathogenic nonsense variants, approximately 20% arise from C-to-T transitions that convert the CGA arginine codon into a UGA stop codon. While recombinant adeno-associated virus (rAAV) has been successfully used to deliver a UAG-targeting sup-tRNA gene in vivo, extending this approach to UGA-targeting sup-tRNA genes has posed unique challenges related to rAAV vector production. Here, we demonstrate that an engineered UGA-sup-tRNA gene, designed with transcriptional regulatory elements, can be efficiently packaged into rAAV for in vivo delivery. A single administration in mouse models of two distinct lysosomal storage disorders restores enzymatic activity to approximately 10% of normal levels. Comparative analysis reveals differential sup-tRNA expression and aminoacylation patterns across tissue types, which correlate with enhanced therapeutic effects. The applied rAAV-based agents and engineering strategies expand the potential therapeutic scope of sup-tRNA therapies.</p>

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An engineered UGA suppressor tRNA gene for disease-agnostic AAV delivery

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月19日

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  • Mengyao Xu,
  • Hao Liu,
  • Jiaming Wang,
  • Andre F. C. Vieira,
  • Xuntao Zhou,
  • Nan Liu,
  • Jialing Liang,
  • Ailing Du,
  • Xiupeng Chen,
  • Ruxiao Xing,
  • Yang Yang,
  • Maria P. Gonzalez-Perez,
  • Vikas Kumar,
  • Dan Wang

摘要

Suppressor transfer RNAs (sup-tRNAs) have the potential to rescue nonsense mutations in a disease-agnostic manner and are an alternative therapeutic approach for many rare and ultrarare disorders. Among all human pathogenic nonsense variants, approximately 20% arise from C-to-T transitions that convert the CGA arginine codon into a UGA stop codon. While recombinant adeno-associated virus (rAAV) has been successfully used to deliver a UAG-targeting sup-tRNA gene in vivo, extending this approach to UGA-targeting sup-tRNA genes has posed unique challenges related to rAAV vector production. Here, we demonstrate that an engineered UGA-sup-tRNA gene, designed with transcriptional regulatory elements, can be efficiently packaged into rAAV for in vivo delivery. A single administration in mouse models of two distinct lysosomal storage disorders restores enzymatic activity to approximately 10% of normal levels. Comparative analysis reveals differential sup-tRNA expression and aminoacylation patterns across tissue types, which correlate with enhanced therapeutic effects. The applied rAAV-based agents and engineering strategies expand the potential therapeutic scope of sup-tRNA therapies.