Charlesworth, C. T. et al. Nat. Med. 25, 249–254 (2019).
Genome editing with the CRISPR–Cas9 system has inspired great hopes for the seamless correction of disease-causing mutations. The ease of the process—delivery of Cas9 and a guide RNA that directs the nuclease to its cleavage site, where the repair process creates or removes mutations—has raised hopes that deleterious human mutations can be fixed with similar ease. Charlesworth et al. now raise the important caveat that Cas9 nucleases often elicit an immune response in humans. The two most commonly used sources of Cas9 are the species Streptococcus pyogenes (Sp) and Staphylococcus aureus (Sa), bacteria that often infect humans. The researchers tested the blood of 125 adult donors for antibodies against the Cas9 species and found that 78% of donors react with SaCas9, and 58% with SpCas9. Furthermore, they showed that 78% and 67% of donors, respectively, showed positive T cell reactivity to the two Cas9 species. These preexisting adaptive immune responses to Cas9 in humans need to be taken into consideration for therapeutic applications of CRISPR.