Scientists have refined a DNA base-editing tool to increase precision and reduce harmful off-target changes. Base-pair editors combine a component that recognises a genome sequence with an enzyme that modifies DNA; these parts are connected by a molecular linker. Earlier editors, including one the group devised in 2020, could edit single cytosines but had trouble when multiple cytosines clustered in patterns such as "CC…CC." Among the tens of thousands of disease-causing C-to-T and T-to-C mutations that this editor type could target, three-quarters involve such clustered cytosines.
The researchers adjusted the linker and weakened the editor's binding to DNA, which reduced its activity on neighbouring bases. In human cell experiments the redesigned editor cut unintended bystander edits dramatically: the most accurate variant decreased bystander mutations by more than 80% while maintaining strong correction at the intended site. At several cystic fibrosis-related genetic sites, unintended edits fell from as high as 50–60% to less than 1% while largely preserving the desired change.
Because cystic fibrosis is caused by mutations in a gene that controls salt and water movement in lung cells, precise single-letter repair could produce longer-lasting benefits than daily drugs. Existing treatments, such as Trikafta, have improved life for many patients but require daily use and can be very costly. The work is still preclinical, but more precise base editors could help make accurate cellular models of rare variants, test drugs and enable more personalised genetic medicine.
- Create accurate cell models of rare variants
- Test potential drugs on those models
- Support more personalised genetic medicine
The research was supported by the National Institutes of Health, the National Science Foundation and the Cystic Fibrosis Foundation. Source: Rice University.
Difficult words
- precision — high degree of accuracy in a measurement or process
- off-target — change that affects unintentional sites in DNA
- linker — molecule that connects two other molecules together
- cytosine — one of the four DNA bases, shown as letter Ccytosines
- bystander edit — an unintended DNA change near the target sitebystander edits
- preclinical — stage of research before testing treatments in humans
- personalised — designed to match a specific person's genetic profile
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Discussion questions
- How might more precise base editors change treatment options for diseases like cystic fibrosis? Give reasons.
- What are the possible benefits and risks of more personalised genetic medicine using precise base editing?
- How could accurate cell models of rare variants help researchers test new drugs or understand disease?
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