Programmed repair of disease-causing UGA premature termination codons in mammalian brain.

Overview

1. Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, United States

Abstract

Protein-truncating variants caused by stop codons are the most prevalent class of rare variant mutations in neurodevelopmental diseases, with UGA codons being most common. Suppressor transfer RNA (sup-tRNA) has therapeutic potential for premature termination codon (PTC) rescue but has thus far underperformed by traditional AAV delivery platforms, and progress has been hampered by the lack of methods to non-invasively assess in vivo activity in mammalian brain. To fill this material gap, we utilize transcranial in vivo bioluminescence imaging data from a luciferase-UGA mouse model to optimize viral payloads with sup-tRNA genes. These data demonstrate that U6 promoter-driven and single-stranded AAV2/9 constructs show variable and dose-dependent activity, whereas self-complementary AAV2/9 with the tRNA in a minimal 100-bp genomic context provides broad and efficacious PTC rescue. Further, payload tRNA multiplexing and use of tRNA introns enable efficacy of low viral titers and sustained rescue. tRNA sequencing of scAAV-delivered ArgUCA sup-tRNA in brain demonstrates no effects on endogenous tRNA levels, their acylation, or processing, and these features are also maintained in the delivered ArgUCA sup-tRNA. Collectively, this work defines a scalable strategy for precision UGA PTC stop codon suppression, supporting development of durable genetic rescue therapies for neurodevelopmental disorders in the mammalian brain.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

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Data

Datasets cited

• geo:GSE334212, at NCBI GEO; found in “Data availability”

Other data links

• ncbi.nlm.nih.gov/geo, NCBI; found in “Data availability”

Data availability

The tRNA sequencing data have been deposited in GEO (https://www.ncbi.nlm.nih.gov/geo/) under accession number GSE334212 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE334212). Custom scripts are available in the Supplementary Data. All relevant data are included within the article and its Supplementary Information files. Requests for further information and resources should be directed to and will be fulfilled by the lead contact, Christopher A. Ahern (E-mail: ).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 3 authors, 10 MeSH terms, 4 funders, 35 references, 1 RRID.

Cite

This paper

Al Saneh, A., Gissot, L., & Ahern, C. A. (2026). Programmed repair of disease-causing UGA premature termination codons in mammalian brain. Nucleic acids research, 54(13), gkag695. https://doi.org/10.1093/nar/gkag695

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