학술논문
A prime editor mouse to model a broad spectrum of somatic mutations in vivo
Document Type
Article
Author
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 M. K.; 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
Source
Nature Biotechnology; March 2024, Vol. 42 Issue: 3 p424-436, 13p
Subject
Language
ISSN
10870156; 15461696
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 Krasmutation associated with drug resistance and Trp53hotspot 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.