David Liu, and a team of scientists has developed an engineered form of Cas9 that can be turned on with a small drug-like molecule. By using this activatable form of Cas9, the team could modify targets in the human genome with up to 25-fold higher specificity than when using the standard form of Cas9. The study is described in an April 6 paper in Nature Chemical Biology.
"This study sought to improve the specificity of genome editing by carefully controlling when Cas9 is active. We engineered a form of Cas9 that is only active in the presence of a harmless, drug-like small molecule which we provide to the cell," Liu explained. "We showed it's possible to achieve efficient genome editing using this system, but because you can stop the production of active Cas9 by withholding the small molecule once it's had enough time to modify the target genes, you limit the opportunity for off-target genome modification."
Insertion of an evolved ligand-dependent intein enables small-molecule control of Cas9.
Nature Chemical Biology - Small molecule–triggered Cas9 protein with improved genome-editing specificity
Directly modulating the activity of genome-editing proteins has the potential to increase their specificity by reducing activity following target locus modification. We developed Cas9 nucleases that are activated by the presence of a cell-permeable small molecule by inserting an evolved 4-hydroxytamoxifen–responsive intein at specific positions in Cas9. In human cells, conditionally active Cas9s modify target genomic sites with up to 25-fold higher specificity than wild-type Cas9.Read more »
Reposted via Next Big Future
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