A new CRISPR genome-editing system has been used to correct sickle-cell anaemia genes in cells – and could be applied widely, it has been announced.
This ‘prime editing’ system, developed by a team from the Broad Institute of MIT and Harvard University, Massachusetts, USA, can directly editing human cells in a precise, efficient, and highly versatile fashion, its developers say.
It differs from previous genome-editing systems because it uses RNA to direct the insertion of new DNA sequences in human cells.
Professor David Liu, of the Broad Institute of MIT and Harvard, said: “With prime editing, we can now directly correct the sickle-cell anaemia mutation back to the normal sequence and remove the four extra DNA bases that cause Tay-Sachs disease, without cutting DNA entirely or needing DNA templates.”
The new prime editing system involves coupling the Cas9 protein – used in CRISPR gene editing – to a reverse transcriptase. The molecular complex uses one strand of the target DNA site to “prime” the direct writing of edited genetic information into the genome.
pegRNA, a new type of engineered guide RNA, directs the prime editor to its target site, where a modified version of the Cas9 protein cuts one strand of the DNA. The pegRNA also contains additional RNA nucleotides encoding the new edited sequence.
The reverse transcriptase element then reads the RNA extension and writes the corresponding DNA nucleotides into the target spot.
“The beauty of this system is that there are few restrictions on the edited sequence,” said Prof Liu. “Since the added nucleotides are specified by the pegRNA, they can be sequences that differ from the original strand by only one letter, that have additional or fewer letters, or that are various combinations of these changes.”
Writing in Nature, the team demonstrates prime editing’s ability, in human cells, to correct gene variants that cause sickle-cell anaemia by converting a specific T to an A, and Tay-Sachs disease, which required the removal of four DNA letters at a precise location in the genome.
They also report further successful edit types in human cells and primary mouse neurons, including all 12 possible ways to replace one DNA letter with another, insertions of new DNA segments up to 44 DNA letters long, precise deletions of up to 80 DNA letters, and modifications combining these different types of edits.
Anzalone, A.V., Randolph, P.B., Davis, J.R., Sousa, A.A., Koblan, L.W., Levy, J.M., Chen, P.J., Wilson, C., Newby, G.A., Raguram, A., Liu, D.R. (2019) “Search-and-replace genome editing without double-strand breaks or donor DNA”, Nature, doi: 10.1038/s41586-019-1711-4
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