Efficient prime editing in mouse brain, liver and heart with dual AAVs

Davis, Jessie R.; Banskota, Samagya; Levy, Jonathan M.; Newby, Gregory A.; Wang, Xiao; Anzalone, Andrew V.; Nelson, Andrew T.; Chen, Peter J.; Hennes, Andrew D; An, Meirui; Roh, Heejin; Randolph, Peyton B.; Musunuru, Kiran; Liu, David R.

doi:10.1038/s41587-023-01758-z

articleNature BiotechnologyMay 4, 2023HYBRID OA

Efficient prime editing in mouse brain, liver and heart with dual AAVs

JRJessie R. Davis SBSamagya Banskota JMJonathan M. Levy GAGregory A. Newby XWXiao Wang

Broad Institute · Howard Hughes Medical Institute · +4 more institutions

PubMed

Indexed incrossrefpubmed

Abstract

Realizing the promise of prime editing for the study and treatment of genetic disorders requires efficient methods for delivering prime editors (PEs) in vivo. Here we describe the identification of bottlenecks limiting adeno-associated virus (AAV)-mediated prime editing in vivo and the development of AAV-PE vectors with increased PE expression, prime editing guide RNA stability and modulation of DNA repair. The resulting dual-AAV systems, v1em and v3em PE-AAV, enable therapeutically relevant prime editing in mouse brain (up to 42% efficiency in cortex), liver (up to 46%) and heart (up to 11%). We apply these systems to install putative protective mutations in vivo for Alzheimer's disease in astrocytes and for…

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Topics & keywords

Topics

Keywords

In vivo
Prime (order theory)
Ex vivo
Biology
Adeno-associated virus
Genome editing
Limiting
Computational biology

UN Sustainable Development Goals

Good health and well-being

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