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

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.

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Publication Details

Journal
Nature Communications
Published
2025-11-28
DOI
https://doi.org/10.1038/s41467-025-65799-5
Primary Topic
Genetic and Kidney Cyst Diseases
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Garth A. Kinberger, Alexander I. Sobolevsky, Francesca Varrone, Laura Y. Yen et al.
Nature Communications
Genetic and Kidney Cyst Diseases
article

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

Garth A. Kinberger, Alexander I. Sobolevsky, Francesca Varrone, Laura Y. Yen, Denis Drygin, Jianfeng Huang, Ronak Lakhia, John W. Ridley, Tate Owen, Scott Davis, Thomas M. Vincent, Carol W. Berman, Maria V. Yelshanskaya, Shanti Pal Gangwar, Vishal Patel, Amin Kamel, Edmund C. Lee, Jesus Alvarez, Tania Valencia, Morgan E. Carlson, Robert W. Kirby, Jessica Mastroianni
article en

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.

Nature CommunicationsVol. 16(1)
Regulus Therapeutics (United States) (US), Columbia University Irving Medical Center (US), Granta Design (United Kingdom) (GB), Berman Center for Outcomes and Clinical Research (US), Columbia University (US), The University of Texas Southwestern Medical Center (US)
U.S. Department of Energy, Oregon Health and Science University, National Institutes of Health, Office of Science, Biological and Environmental Research, SLAC National Accelerator Laboratory, Common Fund
Openalex Percentile: Top 61%
Genetic and Kidney Cyst Diseases
DOIOpen Access PDFOpenAlex
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