In 2016, David Liu and colleagues developed a DNA ‘base editor’—a system that would make it possible to change C•G base pairs to T•A base pairs within DNA without introducing double-stranded breaks. This approach involves tethering of a cytidine deaminase to an inactive RNA-guided Cas9 complex that enables site selectivity. However, this system was unable to correct about half of the single nucleotide polymorphisms that are known to be pathogenic. Now, David Liu and collaborators describe the next step in genomic base editing technology, designed to tackle the conversion of A•T base pairs to G•C base pairs. Beginning with a bacterial adenosine deaminase that acts on RNA, they used seven rounds of selection and refinement to produce ABE7.10. This enzyme, again tethered to an inactive RNA-guided Cas9 complex, uses DNA as a substrate and resulted in an average correction efficiency of 53% across multiple sites and contexts in the genome, with a very low mutagenic background. Importantly, the system can be used both to correct disease-associated single nucleotide polymorphisms and to introduce disease-suppressing ones.
- Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage (Article p464, doi: 10.1038/nature24644)
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