The nucleobase guanine at the 3’-terminus of oligonucleotide RGLS4326 drives off-target AMPAR inhibition and CNS toxicity

Tania Valencia, Laura Y. Yen, Cindy Berman, Thomas Vincent, Scott Davis, Francesca Varrone, Jianfeng Huang, Jessica Mastroianni, Morgan Carlson, Tate Owen, Amin Kamel, Denis Drygin, Garth A. Kinberger, Shanti Pal Gangwar, Maria V. Yelshanskaya, John Ridley, Robert Kirby, Jesus Alvarez, Ronak Lakhia, Vishal Patel, Alexander I. Sobolevsky () and Edmund C. Lee ()
Additional contact information
Tania Valencia: Regulus Therapeutics Inc.
Laura Y. Yen: Columbia University, Department of Biochemistry and Molecular Biophysics
Cindy Berman: Berman Consulting
Thomas Vincent: Regulus Therapeutics Inc.
Scott Davis: Regulus Therapeutics Inc.
Francesca Varrone: Regulus Therapeutics Inc.
Jianfeng Huang: Regulus Therapeutics Inc.
Jessica Mastroianni: Regulus Therapeutics Inc.
Morgan Carlson: Regulus Therapeutics Inc.
Tate Owen: Regulus Therapeutics Inc.
Amin Kamel: Regulus Therapeutics Inc.
Denis Drygin: Regulus Therapeutics Inc.
Garth A. Kinberger: Regulus Therapeutics Inc.
Shanti Pal Gangwar: Columbia University Irving Medical Center, Cellular and Molecular Physiology and Biophysics Graduate Program
Maria V. Yelshanskaya: Columbia University Irving Medical Center, Cellular and Molecular Physiology and Biophysics Graduate Program
John Ridley: Granta Park, Metrion Biosciences Ltd
Robert Kirby: Granta Park, Metrion Biosciences Ltd
Jesus Alvarez: University of Texas Southwestern Medical Center, Department of Internal Medicine and Division of Nephrology
Ronak Lakhia: University of Texas Southwestern Medical Center, Department of Internal Medicine and Division of Nephrology
Vishal Patel: University of Texas Southwestern Medical Center, Department of Internal Medicine and Division of Nephrology
Alexander I. Sobolevsky: Columbia University Irving Medical Center, Cellular and Molecular Physiology and Biophysics Graduate Program
Edmund C. Lee: Regulus Therapeutics Inc.

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Designing safe and effective oligonucleotide (ON) therapeutics requires thorough understanding of structural-activity relationship (SAR) with the intended on-target(s) as well as the unintended off-target(s). Despite encouraging pharmacodynamic activity in a Phase 1b study, development of the first-generation anti-miR-17 ON RGLS4326 for the treatment of autosomal dominant polycystic kidney disease was discontinued due to dose-limiting central nervous system (CNS)-related toxicity observed in nonclinical chronic toxicity studies. Here, we provide SAR evidence that the nucleobase guanine at the 3’-terminus of RGLS4326 drives an unexpected off-target aptamer-like direct interaction with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), thereby causing CNS toxicity. By replacing the 3’-terminal guanine with adenine, we discover the next-generation anti-miR-17 RGLS8429 that is devoid of off-target AMPAR interaction and CNS toxicity while preserving the potency against the on-target miR-17. Here, we show a way to avoid off-target CNS effects and, more importantly, data that support the clinical development of RGLS8429.

Date: 2025
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DOI: 10.1038/s41467-025-65799-5

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