Evasion of Pre-Existing Immunity to Cas9: a Prerequisite for Successful Genome Editing In Vivo?

Purpose of Review CRISPR-Cas9-mediated genome editing holds promise for the future correction of congenital defects in vivo, providing potentially curative interventions for numerous intractable diseases. Nevertheless, the bacterial origin of the Cas9 endonuclease raises the spectre of pre-existing immunity that threatens to undermine the success of this powerful technology, necessitating a careful assessment of the potential risks involved. Recent Findings Given that genome editing commonly exploits the specificity of Cas9 endonucleases from species of bacteria that are a common cause of infection in humans, the recent discovery of neutralising antibodies in the sera of healthy individuals is consistent with pre-existing immunity. Furthermore, the demonstration of T cell responses to Cas9 epitopes suggests that cells and tissues successfully targeted for correction of congenital mutations may be rendered vulnerable to cytotoxic T cell lysis, potentially confounding any future benefits to human health. Summary Although the full impact of pre-existing immunity to Cas9 on the success of in vivo genome editing has yet to be fully determined, it is timely to discuss ways of evading destructive immunity to ensure that its future potential is fully realised.