Journal Article

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

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

2021

Overview

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. Base editors are effective and safe for cholesterol reduction in non-human primates.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/1647/1511 / 631/61/201/2110 / Adenine / Agriculture / Animals / Bioinformatics / Biomedical and Life Sciences / Biomedical Engineering/Biotechnology / Biomedicine / Biotechnology / Cholesterol / Cholesterol, LDL - blood / Cholesterol, LDL - genetics / Deoxyribonucleic acid / DNA / Dosage / Editing / Gene Editing - methods / Genetic aspects / Identification and classification / Immune response / Immune response (humoral) / Life Sciences / Lipids / Liver - metabolism / Liver diseases / Low density lipoprotein / Low density lipoproteins / Macaca / Macaques / Male / Measurement / Mice / Mice, Inbred C57BL / mRNA / Mutation / Nanoparticles / Physiological aspects / Proprotein Convertase 9 - genetics / Reduction / RNA, Guide, CRISPR-Cas Systems