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An improved genome-editing tool to develop advanced gene therapy methods

Lainšček et al., Nature Communications, 2022 

In the field of genome editing technology, we improved the genome modification tool, the CRISPR/Cas system, for which the 2020 Nobel Prize in Chemistry was awarded. The improved system represents significant progress in the development of personalized treatment methods, the study of diseases, biotechnology, and the possibility of personalizing various therapeutic approaches, including the treatment of various cancers and genetic diseases.

The CRISPR/Cas system is a revolutionary tool, that was discovered as a bacterial immune system that protects against bacterial viruses, enables targeted genome editing. This property is used with advantage in research, improved production of food, biofuels, and recently it is gaining importance in the discovery of new drugs and the treatment of various diseases, both cancer and other diseases with a genetic background. The two-component CRISPR/Cas system consists of the Cas9 enzyme and a small RNA that directs the molecular scissors to the specific DNA target sequence that we want to change. Today, there are already more than 60 clinical trials underway to treat many diseases using CRISPR.

The mentioned system with great potential, despite its exceptional usability, can still be improved. The original idea is to connect the Cas9 protein via coiled coil helices to exonucleases, enzymes that shorten the DNA chain from the cleavage site, which we named CCExo. The formation of the coiled coil helix allows the exonuclease to move to the site of the DNA break, resulting in additional removal of nucleotides from both ends of the break. The latter prevents the cell's own mechanisms from repairing the DNA break without change, which improves the proportion of gene knockouts at a specific location. We confirmed the robustness of the CCexo system on many cell lines and different genes.

LAINŠČEK, Duško, FORSTNERIČ, Vida, MIKOLIČ, Veronika, MALENŠEK, Špela, PEČAN, Peter, BENČINA, Mojca, SEVER, Matjaž, PODGORNIK, Helena, JERALA, Roman. Coiled-coil heterodimer-based recruitment of an exonuclease to CRISPR/Cas for enhanced gene editing. Nature communications. 23 Jun. 2022, 13, 1-12. ISSN 2041-1723.


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