| Literature DB >> 34012094 |
Tanja Rothgangl1, Melissa K Dennis2, Paulo J C Lin2, Rurika Oka3, Dominik Witzigmann1, Lukas Villiger1, Weihong Qi4, Martina Hruzova5, Lucas Kissling1, Daniela Lenggenhager6, Costanza Borrelli7, Sabina Egli1, Nina Frey5, Noëlle Bakker1, John A Walker8, Anastasia P Kadina8, Denis V Victorov8, Martin Pacesa9, Susanne Kreutzer4,10, Zacharias Kontarakis4,10, Andreas Moor7, Martin Jinek9, Drew Weissman11, Markus Stoffel5, Ruben van Boxtel3, Kevin Holden8, Norbert Pardi11, Beat Thöny12,13,14, Johannes Häberle12,13,15, Ying K Tam2, Sean C Semple16, Gerald Schwank17,18.
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.Entities:
Year: 2021 PMID： 34012094 DOI： 10.1038/s41587-021-00933-4
Source DB: PubMed Journal: Nat Biotechnol ISSN： 1087-0156 Impact factor: 54.908