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Anti-CRISPR molecules discovered that can block the gene editing technology

Anti-CRISPR molecules discovered that can block the gene editing technology
Newly discovered anti-CRISPR molecules can quickly inhibit the activity of the CRISPR-Cas9 gene editing process
Newly discovered anti-CRISPR molecules can quickly inhibit the activity of the CRISPR-Cas9 gene editing process
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Newly discovered anti-CRISPR molecules can quickly inhibit the activity of the CRISPR-Cas9 gene editing process
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Newly discovered anti-CRISPR molecules can quickly inhibit the activity of the CRISPR-Cas9 gene editing process

As we dive into the brave new world of gene editing, CRISPR technologies are undoubtedly becoming increasingly precise, but alongside enhanced precision is also the necessity for developing ways to inhibit or block the process – an anti-CRISPR molecule, if you will. New work from the Broad Institute and Brigham and Women's Hospital has presented a study that homes in on small molecules that may have the ability to safely block the CRISPR gene editing process.

"Precision control and countermeasures lie at the heart of any powerful technology," explains Amit Choudhary, senior author on the new study. "Consider our ability to harness drugs that induce anesthesia for surgery, and how proper control has turned them into extremely useful tools. Emerging CRISPR technologies, already being developed for gene therapies and biotechnology, likewise will require control across multiple dimensions."

A growing number of researchers are currently working to find effective and safe ways to control, block and even reverse gene editing technologies. DARPA's Safe Genes program has also pumped millions of dollars into trying to develop tools to mitigate the risks of gene editing.

So far, several anti-CRISPR proteins have been identified, but they are not without significant limitations. These proteins are large molecules, often too big to enter cells. They also are not easily reversible, and can be flagged and attacked by the immune system.

The new research set out to find synthetic small-molecule CRISPR inhibitors that are safe, reversible and effectively disrupt the interaction between CRISPR-Cas9 and DNA. After developing a novel screening platform that can closely measure the activity of the CRISPR enzyme within a cell, the researchers screened around 15,000 different potential compounds to find the ones most effective at inhibiting that CRISPR activity.

One particular compound, dubbed BRD0539, stood out for its ability to inhibit the Cas9 enzyme from binding with DNA. The small molecule's activity was dose-dependent, suggesting the degree of inhibition could be fine-tuned in real-time through dosage. The molecule also presented as stable in blood plasma and easily removable, meaning its inhibitory activity could be reversible.

"These results lay the foundation for precise chemical control over CRISPR-Cas9 activities, enabling the safe use of such technologies," says Choudhary. "However, these molecules are not ready for applications in humans and not tested for efficacy in organisms." Choudhary says it is still early days for the research, and this study only presents itself as a proof-of-concept for a screening platform that can identify anti-CRISPR molecules. The next steps for the research will be to better understand how these molecules inhibit CRISPR activity and further optimize their potency and specificity before inevitably looking at whether the process is safe in living organisms.

The new study was published in the journal Cell.

Sources: Broad Institute, Cell Press

1 comment
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Ralf Biernacki
I've always respected DARPA for their forethought. What is being developed here is an antidote against the possible weaponization of CRISPR technology.