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

Author:

Rothgangl TanjaORCID,Dennis Melissa K.,Lin Paulo J. C.,Oka RurikaORCID,Witzigmann DominikORCID,Villiger Lukas,Qi Weihong,Hruzova Martina,Kissling Lucas,Lenggenhager Daniela,Borrelli Costanza,Egli Sabina,Frey Nina,Bakker Noëlle,Walker John A.,Kadina Anastasia P.,Victorov Denis V.,Pacesa MartinORCID,Kreutzer Susanne,Kontarakis ZachariasORCID,Moor AndreasORCID,Jinek MartinORCID,Weissman Drew,Stoffel MarkusORCID,van Boxtel RubenORCID,Holden KevinORCID,Pardi Norbert,Thöny Beat,Häberle Johannes,Tam Ying K.,Semple Sean C.,Schwank GeraldORCID

Abstract

AbstractMost 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.

Publisher

Springer Science and Business Media LLC

Subject

Biomedical Engineering,Molecular Medicine,Applied Microbiology and Biotechnology,Bioengineering,Biotechnology

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