209: PERT: Prime Editing tRNAs for Nonsense Mutations

️ Episode 209: PERT: Prime Editing tRNAs for Nonsense Mutations In this episode of PaperCast Base by Base, we explore how prime editing can reprogram endogenous tRNAs into potent suppressor tRNAs, enabling a single therapeutic strategy to rescue many different genetic diseases caused by premature stop codons. Study Highlights:The authors introduce PERT, a prime editing-mediated strategy that permanently converts selected endogenous tRNAs into optimized suppressor tRNAs capable of reading through premature termination codons. Through large-scale screening of thousands of engineered tRNA variants and careful tuning of promoter, leader, terminator and tRNA sequence elements, they identify sup-tRNAs that efficiently restore protein production even when expressed from a single genomic copy. In human cell models of Batten disease, Tay–Sachs disease, Niemann–Pick type C1 and cystic fibrosis, installation of a single optimized sup-tRNA restores substantial fractions of enzyme activity or full-length protein across many different nonsense mutations. In mouse models, including a Hurler syndrome model carrying a pathogenic stop codon, in vivo delivery of a prime editor that converts a native tRNA into a suppressor tRNA leads to durable enzyme restoration and broad correction of disease pathology, while transcriptome, proteome and off-target analyses show minimal detectable disruption of normal stop codons or global gene expression. Conclusion:This work positions PERT as a promising, disease-agnostic genome-editing platform in which a single, well-characterized prime editing agent could eventually treat diverse genetic disorders caused by nonsense mutations. Music:Enjoy the music based on this article at the end of the episode. Reference:Pierce SE, Erwood S, Oye K, An M, Krasnow N, Zhang E, Raguram A, Seelig D, Osborn MJ, Liu DR. Prime editing-installed suppressor tRNAs for disease-agnostic genome editing. Nature. 2025. https://doi.org/10.1038/s41586-025-09732-2 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com Castos player https://basebybase.castos.com Episode Slug: pert-prime-editing-suppressor-trnas On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Keywords: prime editing, suppressor tRNA, nonsense mutations, therapeutic genome editing, disease-agnostic strategy Chapters (00:00:00) - Genetic precision medicine: The single treatment for thousands of diseases(00:04:27) - Percetic Prime Editing(00:09:54) - PERT for CF-19(00:12:45) - One Code for Many Stars

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