Impact of guanidine-containing backbone linkages on stereopure antisense oligonucleotides in the CNS

Pachamuthu Kandasamy, Yuanjing Liu, Vincent Aduda, Sandheep Akare, Rowshon Alam, Amy Andreucci, David Boulay, Keith Bowman, Michael Byrne, Megan Cannon, Onanong Chivatakarn, Juili Dilip Shelke, Naoki Iwamoto, Tomomi Kawamoto, Jayakanthan Kumarasamy, Sarah Lamore, Muriel Lemaitre, Xuena Lin, Kenneth Longo, Richard Looby, Subramanian Marappan, Jake Metterville, Susovan Mohapatra, Bridget Newman, Ik-Hyeon Paik, Saurabh Patil, Erin Purcell-Estabrook, Mamoru Shimizu, Pochi Shum, Stephany Standley, Kris Taborn, Snehlata Tripathi, Hailin Yang, Yuan Yin, Xiansi Zhao, Elena Dale, Chandra Vargeese

Nucleic Acids Research, gkac037,

In this study, the authors explore the impact of nitrogen-containing (PN) backbones on oligonucleotides that promote RNase H-mediated degradation of a transcript in the central nervous system (CNS). Using Malat1, a ubiquitously expressed non-coding RNA that is predominately localized in the nucleus, and C9orf72, a challenging RNA target requiring a more nuanced targeting strategy, as benchmarks, they show that chimeric oligonucleotides containing stereopure PS and one of the more promising PN backbones (PN-1) have more potent and durable activity throughout the CNS compared with more traditional PS-modified molecules in mouse models. They demonstrate that potency and durability benefits in vivo derive at least in part from increased tissue exposure, especially in more difficult to reach regions of the brain. Ultimately, these benefits enabled the authors to demonstrate pharmacodynamic effects on Malat1 and C9orf72 RNAs in multiple brain regions with relatively low doses.

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