Two molecules could give us finer control over CRISPR gene editing
Health 2 May 2019
By Ruby Prosser Scully
DNA is easily edited using CRISPR
Rostislav Zatonskiy / Alamy Stock Photo
Molecules that act like off switches for CRISPR may one day be used as a drug to make gene editing therapies safer.
The power of CRISPR gene editing to easily change DNA could lead to new treatments for cancers, viral infections, and genetic conditions. But as well as making desirable changes, CRISPR can also make unwanted mutations in DNA, a possible health risk.
"Precision control lies at the heart of powerful technologies," says Amit Choudhary of Harvard University, who has been looking for compounds that can help us more finely control CRISPR. He and his colleagues say they have now identified two promising molecules with the potential to stop the CRISPR-Cas9 enzyme from working within minutes.
To find these, they analysed thousands of molecules, looking for those that could interfere with the enzyme's ability to bind to DNA – a key requirement for being able to identify and alter genes.
Read more: CRISPR gene editing is not quite as precise and as safe as thought
The CRISPR system uses Cas9, an enzyme from bacteria, to bind to DNA and then make a cut in the DNA sequence. The most commonly used version of the CRISPR technique uses a Cas9 enzyme that is constantly switched on, which may raise the risk of it binding other DNA sequences and causing unwanted edits.
But the two molecules identified by Choudhary and his colleagues interfere with the enzyme's ability to recognise and bind to DNA. Choudhary says these should allow scientists to stop the gene-editing process within minutes, thereby reducing the risks of off-target mutations.
Larger anti-CRISPR proteins have previously been developed, but Choudhary says smaller inhibitors are likely to act faster and without prompting an immune response.
When the team tested these molecules in mammalian cell and human plasma, they found that they were non-toxic and didn't appear to disrupt the activity of essential genes.
Nevertheless, the molecules will have to be thoroughly tested to see whether they, themselves, have any unintended effects, Choudhary says.
Journal reference: Cell, DOI: 10.1016/j.cell.2019.04.009
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