Precise gene-editing technique offers hope for inherited diseases
A modification to a gene-editing technique that enables scientists to more precisely recode genetic material could offer hope for currently untreatable inherited diseases. The CRISPR-Cas9 technique, created by the Broad Institute of MIT and Harvard, uses “base editing” to change DNA and RNA molecules. The technique could be used to alter genetic mutations responsible for many diseases. The tool “rewrites” genetic code, rather than deleting and replacing whole strands of DNA. A team of Chinese researchers reported a world-first demonstration of the technique on a human embryo is September.
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.