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High levels of AAV vector integration into CRISPR-induced DNA breaks
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Journal Article
High levels of AAV vector integration into CRISPR-induced DNA breaks
2019
Overview
Adeno-associated virus (AAV) vectors have shown promising results in preclinical models, but the genomic consequences of transduction with AAV vectors encoding CRISPR-Cas nucleases is still being examined. In this study, we observe high levels of AAV integration (up to 47%) into Cas9-induced double-strand breaks (DSBs) in therapeutically relevant genes in cultured murine neurons, mouse brain, muscle and cochlea. Genome-wide AAV mapping in mouse brain shows no overall increase of AAV integration except at the CRISPR/Cas9 target site. To allow detailed characterization of integration events we engineer a miniature AAV encoding a 465 bp lambda bacteriophage DNA (AAV-λ465), enabling sequencing of the entire integrated vector genome. The integration profile of AAV-465λ in cultured cells display both full-length and fragmented AAV genomes at Cas9 on-target sites. Our data indicate that AAV integration should be recognized as a common outcome for applications that utilize AAV for genome editing.
In-depth characterization of adeno-associated virus (AAV)-mediated CRISPR delivery is still lacking. Here, the authors show high levels of integration into Cas9-induced double-strand breaks (DSBs) in therapeutically relevant genes in vivo.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/109
/ 13/44
/ 45/23
/ 631/378
/ 64/60
/ Animals
/ Bacteriophage lambda - genetics
/ Brain
/ Clustered Regularly Interspaced Short Palindromic Repeats
/ Cochlea
/ CRISPR
/ DNA
/ Genome
/ Genomes
/ Humanities and Social Sciences
/ Humans
/ Male
/ Mapping
/ Mice
/ Muscles
/ Nuclease
/ Science
/ Targeted Gene Repair - methods
/ Virus Integration - genetics
/ Viruses
