In vivo adenine base editing of PCSK9 in macaques reduces LDL cholesterol levels

Tanja Rothgangl, Melissa K Dennis, Paulo J C Lin, Rurika Oka, Dominik Witzigmann, Lukas Villiger, Weihong Qi, Martina Hruzova, Lucas Kissling, Daniela Lenggenhager, Costanza Borrelli, Sabina Egli, Nina Frey, Noëlle Bakker, John A Walker, Anastasia P Kadina, Denis V Victorov, Martin Pacesa, Susanne Kreutzer, Zacharias KontarakisAndreas Moor, Martin Jinek, Drew Weissman, Markus Stoffel, Ruben van Boxtel, Kevin Holden, Norbert Pardi, Beat Thöny, Johannes Häberle, Ying K Tam, Sean C Semple, Gerald Schwank

Research output: Contribution to journalArticlepeer-review

Abstract

Most known pathogenic point mutations in humans are C•G to T•A substitutions, which can be directly repaired by adenine base editors (ABEs). In this study, we investigated the efficacy and safety of ABEs in the livers of mice and cynomolgus macaques for the reduction of blood low-density lipoprotein (LDL) levels. Lipid nanoparticle-based delivery of mRNA encoding an ABE and a single-guide RNA targeting PCSK9, a negative regulator of LDL, induced up to 67% editing (on average, 61%) in mice and up to 34% editing (on average, 26%) in macaques. Plasma PCSK9 and LDL levels were stably reduced by 95% and 58% in mice and by 32% and 14% in macaques, respectively. ABE mRNA was cleared rapidly, and no off-target mutations in genomic DNA were found. Re-dosing in macaques did not increase editing, possibly owing to the detected humoral immune response to ABE upon treatment. These findings support further investigation of ABEs to treat patients with monogenic liver diseases.

Original languageEnglish
Pages (from-to)949-957
Number of pages9
JournalNature biotechnology
Volume39
Issue number8
DOIs
Publication statusPublished - Aug 2021

Keywords

  • Adenine
  • Animals
  • Cholesterol, LDL/blood
  • Gene Editing/methods
  • Liver/metabolism
  • Macaca
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Proprotein Convertase 9/genetics
  • RNA, Guide/genetics

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