TwinPE: An improved genome-editing tool that allows inserting entire genes for gene therapy

Researchers at the Broad Institute of Harvard University have just reported in the scientific journal Nature Biotechnology an improved version of prime editing, the highly accurate genome editing method developed in 2019 by the same team. This new version, called twin prime editing (twinPE), allows insertion of DNA fragments of the size of a gene into specific sites of the genome. In the long run, twinPE could be used to design highly precise gene therapies, to replace mutated genes in patients in a safe and targeted manner.

The initial technique allowed the introduction of high precision edits –substitutions, insertions, and deletions of DNA sequences­– into the genome, but only of fragments of several dozen base pairs, which limited its application for gene therapy. Like the original PE, the new version is very precise, because it does not cut the two DNA strands simultaneously, avoiding the introduction of unwanted errors, but also allows to increase substantially the size of the DNA fragments that can be edited. For a detailed explanation of the original PE strategy, see the DBGen blog post from 11/18/2019.

So far, researchers have demonstrated the therapeutic potential of twinPE in human cell cultures in the laboratory, where they have precisely inserted DNA fragments of thousands of base pairs at genomic sites relevant for therapy. They have also managed to reverse the orientation of a 40,000 base pair DNA fragment, showing that it could potentially serve to correct a rare genetic disorder, Hunter syndrome, caused by a genomic alteration with similar characteristics.

In the words of the senior author of the study, David R. Liu: “TwinPE could be a potentially safer and more precise way to insert whole genes of therapeutic interest into positions we specify, such as the location of the native gene in healthy individuals or ‘safe harbor’ sites thought to minimize the risk of side-effects. ”

In another recent study, the same team increased the efficiency of “prime editing”, one additional step for its application as a therapeutic tool. Now, the new twinPE method is a substantial leap forward because it opens the door to inserting, replacing or deleting sequences up to 800 base pairs in length. To insert even larger DNA fragments, the researchers used twinPE to create “landing sites” in the genome, recognized by enzymes called recombinases. By combining TwinPE and recombinase enzymes, gene-sized DNA fragments could be incorporated into these sites.

Currently, David R. Liu and his team continue to work to further increase efficiency and safety of prime editing, to be able to use it in therapeutic applications.

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