A prime editor mouse to model a broad spectrum of somatic mutations in vivo.
Journal
Nature biotechnology
ISSN: 1546-1696
Titre abrégé: Nat Biotechnol
Pays: United States
ID NLM: 9604648
Informations de publication
Date de publication:
Mar 2024
Mar 2024
Historique:
received:
15
07
2022
accepted:
05
04
2023
medline:
18
3
2024
pubmed:
12
5
2023
entrez:
11
5
2023
Statut:
ppublish
Résumé
Genetically engineered mouse models only capture a small fraction of the genetic lesions that drive human cancer. Current CRISPR-Cas9 models can expand this fraction but are limited by their reliance on error-prone DNA repair. Here we develop a system for in vivo prime editing by encoding a Cre-inducible prime editor in the mouse germline. This model allows rapid, precise engineering of a wide range of mutations in cell lines and organoids derived from primary tissues, including a clinically relevant Kras mutation associated with drug resistance and Trp53 hotspot mutations commonly observed in pancreatic cancer. With this system, we demonstrate somatic prime editing in vivo using lipid nanoparticles, and we model lung and pancreatic cancer through viral delivery of prime editing guide RNAs or orthotopic transplantation of prime-edited organoids. We believe that this approach will accelerate functional studies of cancer-associated mutations and complex genetic combinations that are challenging to construct with traditional models.
Identifiants
pubmed: 37169967
doi: 10.1038/s41587-023-01783-y
pii: 10.1038/s41587-023-01783-y
doi:
Substances chimiques
RNA, Guide, CRISPR-Cas Systems
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
424-436Subventions
Organisme : NHLBI NIH HHS
ID : K99 HL163805
Pays : United States
Organisme : NHLBI NIH HHS
ID : R00 HL163805
Pays : United States
Organisme : NHGRI NIH HHS
ID : RM1 HG009490
Pays : United States
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
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