Prime editing, described by Andrew Anzalone in David Liu's laboratory in 2019, has been called a search-and-replace tool for the genome. The system uses a Cas9 nickase fused to an engineered reverse transcriptase, guided by a prime editing guide RNA (pegRNA) that both specifies the target site and encodes the desired edit. After nicking one DNA strand, the reverse transcriptase uses the pegRNA as a template to write the corrected sequence directly into the genome, enabling all twelve types of point mutations plus small insertions and deletions.
Prime Medicine, founded to translate prime editing into therapies, has built a pipeline targeting genetic diseases including chronic granulomatous disease, Wilson disease, and prion disease. The company's platform includes optimized prime editors with improved efficiency and reduced off-target activity. Meanwhile, academic laboratories worldwide have applied prime editing to install precise modifications in a wide range of organisms, from bacteria and yeast to plants and mammalian cells, demonstrating the versatility of the approach across biological contexts.
Technical improvements to prime editing continue at a rapid pace. Twin prime editing and GRAND editing enable large genomic insertions and deletions that were not possible with the original system. PE4 and PE5 variants incorporate DNA mismatch repair inhibition to boost editing efficiency. Delivery remains a key challenge for therapeutic applications, as the large size of the prime editor protein limits packaging in adeno-associated viral vectors, driving interest in mRNA delivery and split-intein approaches that divide the editor across two delivery vehicles.