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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月28日

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  • 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,
  • Edmund C. Lee

摘要

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.