"ONLINE - Ancient CRISPR systems: Evolution towards genome editing"

Who: Borja Alonso, Nanobiotechnology Group

Place: nanoGUNE online webinar

Date: Monday, 1 March 2021, 11:00

Ancient CRISPR systems: Evolution towards genome editing

Borja Alonso

Nanobiotechnology Group, CIC nanoGUNE

The long-awaited goal of genome editing is now a reality thanks to novel tools based on CRISPR-Cas systems. CRISPR-Cas is a revolutionary strategy that allows the possibility of rewriting genes, thus making possible eradicating diseases and disorders with a genetic origin. The native CRISPR-Cas systems provide immunity to prokaryotes responding to invading nucleic acids from infectious genetic elements. Cas proteins guided by CRISPR-encoded RNA molecules (gRNAs) recognize specific regions of the foreign genome and cleave it for inactivation. This has been used for in vivo targeting of DNA of genomes that can be modified. Still, CRISPR is not ready for implementation as therapeutic tool due to limitations such as generation of unwanted mutations at similar loci, production of multiple alleles leading to genetic mosaicism, low efficiency and the induction in the host of an immune response against Cas9. Here, we propose a radically novel approach to generate new Cas enzymes with improved abilities. We use phylogenetic Ancestral Sequence Reconstruction to generate variants of Cas9 from organisms that lived billions of years ago and that were essential for life. Ancestral enzymes have greater stability and efficiency, exhibit chemical promiscuity and are more versatile than their modern descendants. Besides, a remarkable benefit of using ancestral enzymes in gene therapy is that the host?s pre-existing immunity against these proteins can be potentially dismissed.


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