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bioRxiv · 10.64898/2026.07.21.737205

Single anticodon-edited tRNA therapy targeting highly prevalent Arg>Ter premature termination codons causing inherited retinal diseases

Sarma, A. S.·Saleh, A.·Eintracht, J.·Kamal, H.·Khetab, S.·Salameh, M.·Matsevich, C.·Obolensky, A.·Banin, E.·Sharon, D.
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Abstract

Nonsense variants cause 18% of inherited retinal diseases (IRDs), yet current therapies require variant-specific development, leaving most patients untreated. Here, we combined a large-scale genetic analysis literature survey of >37,500 IRD patients with anticodon-edited (ACE)-tRNA engineering to create a single, gene-agnostic therapy targeting Arg>Ter nonsense variants which are the most prevalent subclass (35%) of premature stop codons (PTCs). We developed an optimized ACE-tRNA (V3) that achieved up to 86% readthrough across 13 clinically relevant variants, restored native PRCD localization in the arRP-causing p.R22* mutant, and demonstrated activity in photoreceptor-like cells. To enable translation, we established an AAV2/7m8 production platform (1*10{superscript 1}{superscript 2}-1*10{superscript 1}3 GC/mL) and defined 1*10 GC/eye as the safe dose in mice. This patient genetics-guided strategy positions ACE-tRNA_V3 as a promising candidate for preclinical development, offering a precision medicine approach that targets the most common nonsense variant class with a single therapeutic molecule.

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Sarma, A. S., Saleh, A., Eintracht, J., Kamal, H., Khetab, S., Salameh, M., Matsevich, C., Obolensky, A., Banin, E., Sharon, D.. 2026-07-23. Single anticodon-edited tRNA therapy targeting highly prevalent Arg>Ter premature termination codons causing inherited retinal diseases. https://doi.org/10.64898/2026.07.21.737205

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