| Literature DB >> 35256816 |
Prashant Monian1, Chikdu Shivalila1, Genliang Lu1, Mamoru Shimizu1, David Boulay1, Karley Bussow1, Michael Byrne1, Adam Bezigian1, Arindom Chatterjee1, David Chew1, Jigar Desai1, Frank Favaloro1, Jack Godfrey1, Andrew Hoss1, Naoki Iwamoto1, Tomomi Kawamoto1, Jayakanthan Kumarasamy1, Anthony Lamattina1, Amber Lindsey1, Fangjun Liu1, Richard Looby1, Subramanian Marappan1, Jake Metterville1, Ronelle Murphy1, Jeff Rossi1, Tom Pu1, Bijay Bhattarai1, Stephany Standley1, Snehlata Tripathi1, Hailin Yang1, Yuan Yin1, Hui Yu1, Cong Zhou1, Luciano H Apponi1, Pachamuthu Kandasamy1, Chandra Vargeese2.
Abstract
Technologies that recruit and direct the activity of endogenous RNA-editing enzymes to specific cellular RNAs have therapeutic potential, but translating them from cell culture into animal models has been challenging. Here we describe short, chemically modified oligonucleotides called AIMers that direct efficient and specific A-to-I editing of endogenous transcripts by endogenous adenosine deaminases acting on RNA (ADAR) enzymes, including the ubiquitously and constitutively expressed ADAR1 p110 isoform. We show that fully chemically modified AIMers with chimeric backbones containing stereopure phosphorothioate and nitrogen-containing linkages based on phosphoryl guanidine enhanced potency and editing efficiency 100-fold compared with those with uniformly phosphorothioate-modified backbones in vitro. In vivo, AIMers targeted to hepatocytes with N-acetylgalactosamine achieve up to 50% editing with no bystander editing of the endogenous ACTB transcript in non-human primate liver, with editing persisting for at least one month. These results support further investigation of the therapeutic potential of stereopure AIMers.Entities:
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Year: 2022 PMID： 35256816 DOI： 10.1038/s41587-022-01225-1
Source DB: PubMed Journal: Nat Biotechnol ISSN： 1087-0156 Impact factor: 68.164