Meganuclease targeting of PCSK9 in macaque liver leads to stable reduction in serum cholesterol

Nat Biotechnol. 2018 Sep;36(8):717-725. doi: 10.1038/nbt.4182. Epub 2018 Jul 9.


Clinical translation of in vivo genome editing to treat human genetic diseases requires thorough preclinical studies in relevant animal models to assess safety and efficacy. A promising approach to treat hypercholesterolemia is inactivating the secreted protein PCSK9, an antagonist of the LDL receptor. Here we show that single infusions in six non-human primates of adeno-associated virus vector expressing an engineered meganuclease targeting PCSK9 results in dose-dependent disruption of PCSK9 in liver, as well as a stable reduction in circulating PCSK9 and serum cholesterol. Animals experienced transient, asymptomatic elevations of serum transaminases owing to the formation of T cells against the transgene product. Vector DNA and meganuclease expression declined rapidly, leaving stable populations of genome-edited hepatocytes. A second-generation PCSK9-specific meganuclease showed reduced off-target cleavage. These studies demonstrate efficient, physiologically relevant in vivo editing in non-human primates, and highlight safety considerations for clinical translation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholesterol / blood*
  • Deoxyribonucleases / metabolism*
  • Dependovirus / genetics
  • Gene Editing
  • Genetic Vectors
  • HEK293 Cells
  • Hepatocytes / metabolism
  • Humans
  • Hypercholesterolemia / enzymology
  • Hypercholesterolemia / therapy
  • Induced Pluripotent Stem Cells / metabolism
  • Liver / enzymology*
  • Macaca mulatta
  • Male
  • Mice
  • Mice, Knockout
  • Proprotein Convertase 9 / genetics*
  • Proprotein Convertase 9 / metabolism*
  • Receptors, LDL / antagonists & inhibitors


  • Receptors, LDL
  • Cholesterol
  • Deoxyribonucleases
  • Proprotein Convertase 9