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/

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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.