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

Authors

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

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 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.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 24 Jul 2026.

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