209: PERT: Prime Editing tRNAs for Nonsense Mutations

PERT: Prime Editing tRNAs for Nonsense Mutations Music:Enjoy the music based on this article at the end of the episode. DOI: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 On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/pert-prime-editing-trnas-for-nonsense-mutations ️ Episode:209: PERT: Prime Editing tRNAs for Nonsense Mutations ️ Season:1 Article title:Prime editing-installed suppressor tRNAs for disease-agnostic genome editing Journal:Nature QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-25. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantively audited the central scientific narrative: PERT concept and single-locus sup-tRNA installation; cell-model rescues in Batten/Tay-Sachs/NPC1; ClinVar PTC readthrough breadth; in vivo GFP reporter readthrough; Hurler mouse model IDUA restoration and pathology rescue; safety/off-target and delivery considerat- transcript topics: Disease-agnostic genome editing concept (PERT); Sup-tRNA optimization and design (leader, body, terminator); Single-locus endogenous tRNA installation via prime editing; Cell-model rescues: Batten (TPP1), Tay-Sachs (HEXA), NPC1; ClinVar PTC readthrough across 14,746 mutations; In vivo GFP reporter readthrough and Hurler syndrome mouse model QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 7- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- PERT installs an engineered sup-tRNA at a single endogenous genomic locus to enable readthrough of premature termination codons (PTCs).- In human cell models of Batten (TPP1), Tay–Sachs (HEXA), and Niemann–Pick (NPC1) diseases, treatment with the same prime editor components restored 20–70% of normal enzyme activity- In a Hurler syndrome mouse model, IDUA enzyme activity was restored ~6% and disease pathology was nearly completely rescued.- Across ClinVar PTCs (14,746 tested), readthrough was observed for the vast majority, with an average readthrough score of 69% ± 30%.- Mass spectrometry indicated no detectable readthrough of natural termination codons (NTCs) and no broad perturbations to the transcriptome or proteome.- In vivo GFP reporter readthrough in a reporter mouse was around 25% full-length GFP production with the PERT approach. QC result: Pass. 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