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    Engineered CRISPR-Cas9 with “zero” off-target noise

    A newly engineered version of the gene-editing CRISPR-Cas9 nuclease appears to robustly abolish the unwanted, off-target DNA breaks that are a significant current limitation of the technology, reducing them to undetectable levels. In their recent report in Nature on Jan 6th, Massachusetts General Hospital (MGH) researchers describe how altering the Cas9 enzyme to reduce non-specific interactions with the target DNA may greatly expand applications of the gene-editing technology.
    The team focused on the fact that certain portions of the Cas9 enzyme can interact with the backbone of the target DNA molecule. Pursuing an observation originally made by co-lead author Vikram Pattanayak, M.D., Ph.D., of MGH Pathology, the team altered four of these Cas9-mediated contacts by replacing the long amino acid side-chains that bind to the DNA backbone with shorter ones unable to make those connections.
    Previous work from the Joung lab published last summer in Nature had shown that introducing a series of amino acid substitutions could expand the targeting range of unaltered SpCas9. In the current study, the authors show that introducing these same alterations into SpCas9-HF1 (high fidelity) also extended the targeting range of the high-fidelity variant.