| Autor: |
Mark K Schlegel, Maja M Janas, Yongfeng Jiang, Joseph D Barry, Wendell Davis, Saket Agarwal, Daniel Berman, Christopher R Brown, Adam Castoreno, Sarah LeBlanc, Abigail Liebow, Tara Mayo, Stuart Milstein, Tuyen Nguyen, Svetlana Shulga-Morskaya, Sarah Hyde, Sally Schofield, John Szeto, Lauren Blair Woods, Vedat O Yilmaz, Muthiah Manoharan, Martin Egli, Klaus Charissé, Laura Sepp-Lorenzino, Patrick Haslett, Kevin Fitzgerald, Vasant Jadhav, Martin A Maier |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Nucleic acids research. 50(12) |
| ISSN: |
1362-4962 |
| Popis: |
Preclinical mechanistic studies have pointed towards RNA interference-mediated off-target effects as a major driver of hepatotoxicity for GalNAc–siRNA conjugates. Here, we demonstrate that a single glycol nucleic acid or 2′–5′-RNA modification can substantially reduce small interfering RNA (siRNA) seed-mediated binding to off-target transcripts while maintaining on-target activity. In siRNAs with established hepatotoxicity driven by off-target effects, these novel designs with seed-pairing destabilization, termed enhanced stabilization chemistry plus (ESC+), demonstrated a substantially improved therapeutic window in rats. In contrast, siRNAs thermally destabilized to a similar extent by the incorporation of multiple DNA nucleotides in the seed region showed little to no improvement in rat safety suggesting that factors in addition to global thermodynamics play a role in off-target mitigation. We utilized the ESC+ strategy to improve the safety of ALN-HBV, which exhibited dose-dependent, transient and asymptomatic alanine aminotransferase elevations in healthy volunteers. The redesigned ALN-HBV02 (VIR-2218) showed improved specificity with comparable on-target activity and the program was reintroduced into clinical development. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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