Amplified genome editing by in vivo editor production

Abstract

Genome editing enzymes have vast therapeutic potential. However, achieving sufficient delivery in vivo remains a major challenge, because editing machinery is confined to the subset of transfectable cells in a tissue. Here, we tested the possibility that genome editing could be amplified in vivo by enabling transfected cells to transfer editing enzymes to neighboring cells. Our data show that this NANoparticle-Induced Transfer of Enzyme (NANITE) strategy quadrupled editing efficiency in cultured cells relative to non-spreading controls. A single intravenous injection of the NANITE plasmid into mice induced ~3-fold higher levels of liver editing at the transthyretin (Ttr) locus relative to non-spreading controls, with corresponding reductions in serum TTR levels. Spreading therapeutic enzymes offers a nonviral and non-infectious strategy to boost therapeutic effects after delivery.