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Gene Therapy

Gene Editing Moves Closer To The Clinic As The Safest CRISPR System Yet Is Announced

Posted on 9 January 2016

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In an exciting breakthrough, researchers have announced a high fidelity CRISPR-Cas9 version that displays no detectable off-target activity – meaning it could reassure concerns over inaccuracy. 

The Coming Gene Editing Boom

You might be sick of hearing about CRISPR-Cas9 and all the hype around the world of gene editing, but courtesy of massive interest and investment prospects are looking better than ever for the budding technology. 

CRISPR-Cas9 is already an effective system, having been demonstrated to great effect in laboratory experiments already, but for human use we need better than good. When you’re dealing with DNA, you need essentially perfect accuracy to pass safety concerns.

There are a number of versions beyond the ‘original classic’ form that are being explored in a number of studies – essentially being tailored to the scientist’s need. Within this bunch a new version of the system has emerged, that encouragingly has undetectable levels of off-target activity.

“Our creation of a Cas9 variant that brings off-target effects to levels where we can no longer detect them, even with the most sensitive methods, provides a substantial advance for therapeutic applications in which you want to accurately hit your target without causing damage anywhere else in the genome. As a result, we envision that our high-fidelity variant will supplant the use of standard Cas9 for many research and therapeutic applications” 

Credit: McGovern Institute for Brain Research at MIT

Credit: McGovern Institute for Brain Research at MIT

What’s new?

The new improved version of the technology is a result of attempts to reduce the strength the nuclease will ‘grab’ DNA. Guided by a sequence of RNA to match a DNA sequence, the trailing Cas9 enzyme will bind and hold sequences with the right molecular pattern. While it does a great job doing this with sequences you want it to hit, in the past it’s also been shown to bind at other sites too. There have been doubts of its ability to ‘snip’ at off-target sites, but any unwanted cut in your genome could have disastrous consequences. Reducing this off-target binding has been a priority because of these fears.

“Our previous work suggested that Cas9 might bind to its intended target DNA site with more energy than it needs, enabling unwanted cleavage of imperfectly matched off-target sites,” explained Dr. Pattanayak. “We reasoned that, by making substitutions at these four positions, we could remove some of that energy to eliminate off-target effects while still retaining full on-target activities”

In order to perfect the system, the researchers tested 15 different forms with subtle amino acid changes in its sequence. They eventually settled on a promising version called SpCas9-HF1, which had 4 unique amino acid side chains substitutions. After further tweaking of this type, they were able to hone the accuracy even further. 

Although the new system is not entirely ‘perfect’, if such a thing can exist, in comparison to the ‘wild’ version it has unparalleled accuracy. Furthermore, the researchers hope by tweaking the system further they can improve it even more. 

“With its exceptional precision, SpCas9-HF1 provides an alternative to wild-type SpCas9 for research and therapeutic applications. More broadly, our results suggest a general strategy for optimizing genome-wide specificities of other CRISPR-RNA-guided nucleases”

Read more at GEN News

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