[News & Views]Towards therapeutic base editing
Authors and Affiliations
The vast majority of genetic diseases are caused by single-nucleotide mutations rather than chromosomal rearrangements or small insertions or deletions (indels) and hence could potentially be therapeutically targeted by base editing. RNA-programmable deaminases, known as base editors (BEs), enable single-nucleotide cytosine-to-thymine or adenine-to-guanine conversions in a small guide RNA (sgRNA)-dependent manner in cultured cells1,2,3,4 and organisms5,6,7,8,9 and are hence well-suited to treating genetic diseases caused by single-nucleotide mutations. These BEs comprise a catalytically deficient CRISPR-Cas9 or CRISPR-CPF1 variant, derived from the two most widely used gene editing enzymes, or a Cas9 nickase variant fused to a cytosine or adenine deaminase. Unlike Cas9 or CPF1 nucleases, BEs in principle do not produce indels and do not require a donor DNA template because base editing does not rely on mutagenic nonhomologous end joining (NHEJ) or inefficient homology-directed repair (HDR) in nondividing cells, making them powerful tools for gene correction and targeted mutagenesis in vivo (Fig. 1).