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TitleThe nucleobase guanine at the 3'-terminus of oligonucleotide RGLS4326 drives off-target AMPAR inhibition and CNS toxicity.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 10762, Year 2025
Publish dateNov 28, 2025
AuthorsTania 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 /
PubMed AbstractDesigning 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- ...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.
External linksNat Commun / PubMed:41315228 / PubMed Central
MethodsEM (single particle)
Resolution3.24 Å
Structure data

47792

9e9d

EMDB-47792, PDB-9e9d:
Structure of full length AMPA receptor GluA2 and auxiliary subunit TARP gamma-2 in complex with anti-miR 17 oligonucleotide RGLS4326
Method: EM (single particle) / Resolution: 3.24 Å

47793

9e9e

EMDB-47793, PDB-9e9e:
Structure of AMPA receptor GluA2 and auxiliary subunit TARP gamma-2 (LBD-TMD) in complex with anti-miR 17 oligonucleotide RGLS4326
Method: EM (single particle) / Resolution: 3.24 Å

Chemicals

PDB-1bx3:
EFFECTS OF COMMONLY USED CRYOPROTECTANTS ON GLYCOGEN PHOSPHORYLASE ACTIVITY AND STRUCTURE

Source
  • rattus norvegicus (Norway rat)
KeywordsSIGNALING PROTEIN / AMPA receptor / TARP gamma-2 / ion channel / anti-miR 17 / oligonucleotide

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