In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates

Gene-editing technologies, including CRISPR-Cas nucleases and CRISPR base editors, have the potential to permanently modify disease-causing genes in human patients. The demonstration of durable editing in target organs of non-human primates (NHPs) is a key step prior to in vivo administration of gene editors to patients in clinical trials. Here we demonstrate that CRISPR base editors delivered in vivo using lipid nanoparticles (LNP) can efficiently and precisely modify disease-related genes in living NHPs. We observed near-complete knockdown of PCSK9 in the liver following a single infusion of LNP, with a concomitant ~90% reduction in blood PCSK9 protein and ~60% reduction in blood low-density lipoprotein cholesterol (LDL-C), all of which remain stable for at least 8 months following a single-dose treatment. In addition to supporting a once-and-done approach to reduce LDL-C and treat atherosclerotic cardiovascular disease, the leading cause of death worldwide, our results provide a proof-of-concept for how CRISPR base editors can be productively applied to make precise single-nucleotide changes in therapeutic target genes in the liver and potentially other organs.