UZH develops new compact gene scissor

A research team from UZH led by Gerald Schwank from the Institute of Pharmacology and Toxicology has successfully further developed gene scissors technology in partnership with colleagues from the Swiss Federal Institute of Technology in Zurich. This technology is able to directly repair gene defects at the genome. The new approach focuses on the protein TnpB, which is far smaller than the CRISPR-Cas systems that use Cas proteins. Their size is a problem when it comes to transporting them to the correct cells in the body.

It was recently discovered that Cas proteins in evolutionary biology evolved from much smaller proteins. For example, TnpB is the forerunner to Cas12. Therefore, recent studies have sought to use these much smaller evolutionary ancestors as genome editing tools. However, this approach works less efficiently than CRISPR-Cas. But the research team has now solved this problem: “By engineering the small but powerful protein TnpB, we were able to design a variant that shows a 4.4-fold increase in efficiency of modifying DNA – making it more effective as a gene editing tool”, as Schwank states in an article published by the university.

“The trick was to modify the tool in two ways: first, so that it more efficiently goes to the nucleus where the genomic DNA is located, and second, so that it also targets alternative genome sequences”, comments Kim Marquart, a PhD student and first author of the study. An Artificial Intelligence model that the team developed together with UZH professor Michael Krauthammer has the ability to predict “how well TnpB will work in different scenarios”, Marquart adds.

The team has successfully edited genes with the TnpB tool in experiments carried out on mice that reduce cholesterol in patients with hypercholesterolemia by nearly 80 percent. According to Gerald Schwank, the aim is now “to develop similar gene editing strategies in humans”. ce/mm