“New ‘Prime’ Genome Editor Could Surpass CRISPR”, 2019-10-21 ():
CRISPR, an extraordinarily powerful genome-editing tool invented in 2012, can still be clumsy. It sometimes changes genes it shouldn’t, and it edits by hacking through both strands of DNA’s double helix, leaving the cell to clean up the mess—shortcomings that limit its use in basic research and agriculture and pose safety risks in medicine. But a new entrant in the race to refine CRISPR promises to steer around some of its biggest faults. “It’s a huge step in the right direction”, chemist George Church, a CRISPR pioneer at Harvard University, says about the work, which appears online today in Nature.
…Liu’s earlier handwork, base editing, does not cut the double-stranded DNA but instead uses the CRISPR targeting apparatus to shuttle an additional enzyme to a desired sequence, where it converts a single nucleotide into another. Many genetic traits and diseases are caused by a single nucleotide change, so base editing offers a powerful alternative for biotechnology and medicine. But the method has limitations, and it, too, often introduces off-target mutations.
Prime editing steers around shortcomings of both techniques by heavily modifying the Cas9 protein and the guide RNA. The altered Cas9 only “nicks” a single strand of the double helix, instead of cutting both. The new guide, called a pegRNA, contains an RNA template for a new DNA sequence, to be added to the genome at the target location. That requires a second protein, attached to Cas9: a reverse transcriptase enzyme, which can make a new DNA strand from the RNA template and insert it at the nicked site.
Liu, who has already formed a company around the new technology, Prime Medicine, stresses that to gain a place in the editing toolkit, it will have to prove robust and useful in many labs. Delivering the large construct of RNA and enzymes into living cells will also be difficult, and no one has yet shown it can work in an animal model.