Oligonucleotide-directed RNA editing in primates

Abstract

Recent approvals of antisense, exon skipping, and small interfering RNA (siRNA) therapeutics, along with the highly successful mRNA-based COVID-19 vaccines, have invigorated the field of nucleic acid therapeutics and stimulated interest in other mechanisms by which oligonucleotides might elicit therapeutic effects. 1 Damase T.R. Sukhovershin R. Boada C. Taraballi F. Pettigrew R.I. Cooke J.P. The limitless future of RNA therapeutics. Front. Bioeng. Biotechnol. 2021; 9: 628137 Crossref PubMed Scopus (91) Google Scholar Oligonucleotides can be used to guide Adenosine Deaminases Acting on RNA (ADARs) to correct disease-causing mutations, suggesting the possibility of therapeutic RNA editing. 2 Woolf T.M. Chase J.M. Stinchcomb D.T. Toward the therapeutic editing of mutated RNA sequences. Proc. Natl. Acad. Sci. U S A. 1995; 92: 8298-8302https://doi.org/10.1073/pnas.92.18.8298 Crossref PubMed Scopus (58) Google Scholar , 3 Qu L. Yi Z. Zhu S. Wang C. Cao Z. Zhou Z. Yuan P. Yu Y. Tian F. Liu Z. et al. Programmable RNA editing by recruiting endogenous ADAR using engineered RNAs. Nat. Biotechnol. 2019; 37: 1059-1069https://doi.org/10.1038/s41587-019-0178-z Crossref PubMed Scopus (86) Google Scholar , 4 Merkle T. Merz S. Reautschnig P. Blaha A. Li Q. Vogel P. Wettengel J. Li J.B. Stafforst T. Precise RNA editing by recruiting endogenous ADARs with antisense oligonucleotides. Nat. Biotechnol. 2019; 37: 133-138https://doi.org/10.1038/s41587-019-0013-6 Crossref PubMed Scopus (104) Google Scholar , 5 Katrekar D. Chen G. Meluzzi D. Ganesh A. Worlikar A. Shih Y.-R. Varghese S. Mali P. In Vivo RNA editing of point mutations via RNA-guided adenosine deaminases. Nat. Methods. 2019; 16: 239-242https://doi.org/10.1038/s41592-019-0323-0 Crossref PubMed Scopus (75) Google Scholar The manuscript by Monian and Shivalila et al. recently published in Nature Biotechnology describes the recruitment of endogenously expressed ADARs with short, chemically modified oligonucleotides (AIMers) for efficient directed RNA editing in non-human primates (NHPs) for the first time. Importantly, the authors show that a fully modified 30-nucleotide (nt) AIMer bearing GalNAc to facilitate liver uptake yielded 50% target transcript editing without measurable off-target editing. 6 Monian P. Shivalila C. Lu G. Shimizu M. Boulay D. Bussow K. Byrne M. Bezigian A. Chatterjee A. Chew D. et al. Endogenous ADAR-mediated RNA editing in non-human primates using stereopure chemically modified oligonucleotides. Nat. Biotechnol. 2022; https://doi.org/10.1038/s41587-022-01225-1 Crossref PubMed Scopus (7) Google Scholar This advance sets the stage for translation of oligonucleotide-directed RNA editing technologies to the clinic.