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Precision Engineering of the Genome, Epigenome and Transcriptome | EK24


A versatile platform for ADAR-mediated RNA editing in vivo in preclinical models


Mar 8, 2021 12:00am ‐ Mar 8, 2021 12:00am

Description

A versatile platform for ADAR-mediated RNA editing in vivo in preclinical models Chikdu Shivalila1, Prashant Monian1, Genliang Lu1, Bijay Bhattarai1, 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, Pachamuthu Kandasamy1, Anthony Lamattina1, Amber Lindsey1, Fangjun Liu1, Richard Looby1, Jake Metterville1, Ronelle Murphy1, Jeff Rossi1, Stephany Standley1, Snehlata Tripathi1, Hailin Yang1, Yuan Yin1, Hui Yu1, Cong Zhou1, Luciano Apponi1, Chandra Vargeese1 1Wave Life Sciences, Cambridge, MA, USA The ADAR (adenosine deaminases acting on RNA) family of enzymes catalyze adenine (A) to inosine (I) changes in RNA, which are read as guanine (G) by the translational machinery. Recruiting endogenous ADAR enzymes using chemically modified oligonucleotides to direct specific editing holds great promise for treating human disease. PRISMTM, Wave Life Sciences’ proprietary discovery and drug development platform, enables us to develop stereopure oligonucleotides—those in which the chiral configuration of backbone linkages (Rp or Sp) are precisely controlled at each position—that direct sequence-specific RNA editing using endogenous ADAR enzymes. We will present preclinical in vivo data in mouse and non-human primates (NHPs) showing that stereopure oligonucleotides are effective when delivered as naked oligonucleotides or GalNAc-conjugates in the absence of any delivery vehicle via systemic, intracerebroventricular or intrathecal administration. We show editing in myriad tissues, including liver, multiple regions of the CNS, kidney and lung. The most promising oligonucleotides support up to 50% editing in vivo. These preclinical investigations lay the foundation for development of RNA-editing therapeutics with potential to treat human genetic disease.

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