Eliminating base-editor-induced genome-wide and transcriptome-wide off-target mutations
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A new gene-editing tool allows researchers to rewrite individual letters of DNA, or genetic bases, with lower risk of off-target activity.
CRISPR–Cas9 technology is an incredibly powerful way to edit genes, but it sometimes causes unintended edits in off-target regions.
Devised by researchers at ShanghaiTech University, the new gene-editing method could allow for safe and effective correction of disease-causing mutations or the precise manipulation of genes for therapeutic gain.
The system uses a base-editing enzyme tethered to a counteracting ‘antidote’ protein. When the tool binds at target sites, the antidote is cleaved off and the base editor alters the desired DNA — swapping one base for another — without introducing unintended mutations.
The researchers used their base-editing method in mice to create shortened versions of PCSK9, a protein involved in cholesterol metabolism. The mice subsequently had lower levels of cholesterol in their blood, with no detectable off-target mutations in either their DNA or RNA.
- Nature Cell Biology 23, 552–563 (2021). doi: 10.1038/s41556-021-00671-4