Stereo-random oligonucleotides enable efficient recruitment of ADAR in vitro and in vivo

Laura S. Pfeiffer, Tobias Merkle, Paul Vogel, Inga Jarmoskaite, Jonathan M. Geisinger, Ngadhnjim Latifi, Marco Herrera-Barrera, Feijie Zhang, Lisa Groß, Carolin Schlitz, Daniel T. Hofacker, Clemens Lochmann, Davide Fumagalli, Stefanie Gackstatter, Vanessa Deisling, Mark A. Kay, Jin Billy Li and Thorsten Stafforst ()
Additional contact information
Laura S. Pfeiffer: University of Tübingen
Tobias Merkle: University of Tübingen
Paul Vogel: Stanford University
Inga Jarmoskaite: Stanford University
Jonathan M. Geisinger: Stanford University
Ngadhnjim Latifi: University of Tübingen
Marco Herrera-Barrera: Stanford University
Feijie Zhang: Stanford University
Lisa Groß: University of Tübingen
Carolin Schlitz: University of Tübingen
Daniel T. Hofacker: University of Tübingen
Clemens Lochmann: University of Tübingen
Davide Fumagalli: University of Tübingen
Stefanie Gackstatter: University of Tübingen
Vanessa Deisling: University of Tübingen
Mark A. Kay: Stanford University
Jin Billy Li: Stanford University
Thorsten Stafforst: University of Tübingen

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Site-directed RNA editing is a promising and potentially safer alternative to genome editing. Previous methods have been developed that recruit the endogenously and ubiquitously expressed ADAR enzymes to initiate site-specific A-to-I edits, but often suffer from low efficacy or dependency on viral delivery. Chemically modified oligonucleotides may be a promising alternative, but the approach still lacks systematic in-depth studies. Furthermore, the best characterized platform uses stereo-pure backbone chemistry, which is not widely used, commercially unavailable and challenging to manufacture. Here, we report on single-stranded oligonucleotides of 30-60 nt length, which are fully chemically stabilized by applying commercially available, classical RNA drug modifications, like 2´-O-methyl, 2´-fluoro, and DNA on a stereo-random phosphate/phosphorothioate backbone. We demonstrate our so-called RESTORE 2.0 oligonucleotides to induce the correction of pathogenic point mutations, efficacy after GalNAc-mediated uptake into human primary hepatocytes, and proof of in-vivo efficacy in mice upon lipid nanoparticle-mediated delivery. The discovered design principles may increase the accessibility of site-directed RNA base editing to expand and support further research in this field.

Date: 2025
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DOI: 10.1038/s41467-025-64434-7

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