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 core scientific narrative: disease-burden framing, PERT mechanism, sup-tRNA optimization, endogenous-locus installation, cell-model rescues (Batten/Tay-Sachs/NPC1), Hurler in vivo outcomes, ClinVar readthrough scope, safety/off-target analyses, and delivery considerations.- transcript topics: Disease burden and need for disease-agnostic therapy; PERT concept: suppressor tRNA readthrough; sup-tRNA optimization: leader, body, terminator; saturation mutagenesis; Single-locus endogenous tRNA installation via prime editing; In vitro rescue in Batten (TPP1), Tay-Sachs (HEXA), NPC1 models; ClinVar PTC readthrough across 14,746 cases 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:- One-step endogenous installation of optimized sup-tRNA at a single genomic locus via PE (PERT).- In human cell models, 20–70% restoration of normal enzyme activity for Batten (TPP1), Tay–Sachs (HEXA), and Niemann–Pick (NPC1).- Hurler syndrome mouse model showed ≈6% IDUA enzyme activity restoration and near-complete rescue of pathology.- Broad readthrough across ClinVar PTCs: 69% ± 30% readthrough score across 14,746 pathogenic PTCs.- Off-target editing not observed above background in genome-wide analyses; no significant off-target events detected.- No detectable readthrough of natural stop codons (NTCs) or major transcriptome/proteome perturbations. 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