A prime editor mouse to model a broad spectrum of somatic mutations in vivo

Ely, Zackery A, Mathey-Andrews, Nicolas, Naranjo, Santiago, Gould, Samuel I, Mercer, Kim L, Newby, Gregory A, Cabana, Christina M, Rideout, William M, Jaramillo, Grissel Cervantes, Khirallah, Jennifer M, Holland, Katie, Randolph, Peyton B, Freed-Pastor, William A, Davis, Jessie R, Kulstad, Zachary, Westcott, Peter MK, Lin, Lin, Anzalone, Andrew V, Horton, Brendan L, Pattada, Nimisha B, Shanahan, Sean-Luc, Ye, Zhongfeng, Spranger, Stefani, Xu, Qiaobing, Sánchez-Rivera, Francisco J, Liu, David R, Jacks, Tyler (May 2023) A prime editor mouse to model a broad spectrum of somatic mutations in vivo. Nature Biotechnology. ISSN 1087-0156 (Public Dataset)

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Abstract

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.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics Investigative techniques and equipment organism description > animal Investigative techniques and equipment > CRISPR-Cas9 organism description > animal > mammal organism description > animal > mammal > rodent > mouse bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations organism description > animal > mammal > rodent
CSHL Authors:	Westcott, Peter
Communities:	CSHL Cancer Center Program CSHL Cancer Center Program > Cancer Genetics and Genomics Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	11 May 2023
Date Deposited:	21 Sep 2023 14:47
Last Modified:	03 Jul 2024 16:04
PMCID:	PMC11120832
Related URLs:	Publisher
Dataset ID:	SRA: PRJNA951647
URI:	https://repository.cshl.edu/id/eprint/40937

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