New Gene Editing Tool Is Smaller and Better than CRISPR

Scientists at Cornell University have advanced toward a new gene editing tool. It is less than half the size of CRISPR-Cas9, which is currently the most reliable genome editing system. This new tool would allow scientists to fit genetic editors into smaller viral delivery systems to fix a variety of diseases.

CRISPR-Cas9 tools need to be effectively delivered into every cell of the patient. And most Cas9s are too big to fit into popular genome therapy vectors, such as the Adenovirus-Associated Viruses (AAV).

AAV don’t seem to cause diseases but only mild immune responses. And they are often used to create viral vectors for gene therapy.

"Next-generation fancy applications require the gene editor to be fused with other enzymes and activities and most Cas9s are already too big for viral delivery. We are facing a traffic jam at the delivery end," says researcher Ailong Ke in a press release issued by Cornell University.

"If Cas9s can be packaged into viral vectors that have been used for decades in the gene therapy field, like AAV, then we can be confident they can be delivered and we can focus research exclusively on the efficacy of the editing tool itself."

The researchers suggest that nature uses transposons (mobile genetic elements inside bacteria) to deliver gene editing tools to cells. Transposons are believed to be evolutionary precursors to CRISPR systems.

"Transposons are specialized genetic hitchhikers, integrating into and splicing out of our genomes all the time," adds Ke. "The systems inside bacteria in particular are being selected constantly - nature has basically tossed the dice billions of times and come up with really powerful DNA surgical tools, CRISPR included. And now, by defining these enzymes in high resolution, we can tap into their powers."

CRISPR-Cas9 systems use an RNA as a guide to recognize a sequence of DNA. When a match is found, the Cas9 protein snips the target DNA at just the right place. It's then possible to do surgery at the DNA level to fix genetic diseases.

A paper is published in Science. The researchers report that they used high resolution cryo-electron microscopy (Cryo-EM) to study IscB, a molecule found in transposons.

"It's about understanding the molecules' structure and how they perform the chemical reactions," says researcher Gabriel Schuler. "Studying these transposons gives us a new starting point to generate more powerful and accessible gene editing tools."

It turns out that IscB works like Cas9 but has a smaller size. Therefore, replacing Cas9 with IscB would solve the size problem.

The researchers were even able to engineer slimmer IscB variants, by removing nonessential parts from IscB. They've already removed 55 amino acids without affecting IscB's activity. And they hope to make future versions of this genome editor even smaller and hence even more useful.