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Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity

Author

Listed:
  • Maja M. Janas

    (Alnylam Pharmaceuticals)

  • Mark K. Schlegel

    (Alnylam Pharmaceuticals)

  • Carole E. Harbison

    (Alnylam Pharmaceuticals)

  • Vedat O. Yilmaz

    (Alnylam Pharmaceuticals)

  • Yongfeng Jiang

    (Alnylam Pharmaceuticals)

  • Rubina Parmar

    (Alnylam Pharmaceuticals)

  • Ivan Zlatev

    (Alnylam Pharmaceuticals)

  • Adam Castoreno

    (Alnylam Pharmaceuticals)

  • Huilei Xu

    (Alnylam Pharmaceuticals)

  • Svetlana Shulga-Morskaya

    (Alnylam Pharmaceuticals)

  • Kallanthottathil G. Rajeev

    (Alnylam Pharmaceuticals)

  • Muthiah Manoharan

    (Alnylam Pharmaceuticals)

  • Natalie D. Keirstead

    (Alnylam Pharmaceuticals)

  • Martin A. Maier

    (Alnylam Pharmaceuticals)

  • Vasant Jadhav

    (Alnylam Pharmaceuticals)

Abstract

Small interfering RNAs (siRNAs) conjugated to a trivalent N-acetylgalactosamine (GalNAc) ligand are being evaluated in investigational clinical studies for a variety of indications. The typical development candidate selection process includes evaluation of the most active compounds for toxicity in rats at pharmacologically exaggerated doses. The subset of GalNAc-siRNAs that show rat hepatotoxicity is not advanced to clinical development. Potential mechanisms of hepatotoxicity can be associated with the intracellular accumulation of oligonucleotides and their metabolites, RNA interference (RNAi)-mediated hybridization-based off-target effects, and/or perturbation of endogenous RNAi pathways. Here we show that rodent hepatotoxicity observed at supratherapeutic exposures can be largely attributed to RNAi-mediated off-target effects, but not chemical modifications or the perturbation of RNAi pathways. Furthermore, these off-target effects can be mitigated by modulating seed-pairing using a thermally destabilizing chemical modification, which significantly improves the safety profile of a GalNAc-siRNA in rat and may minimize the occurrence of hepatotoxic siRNAs across species.

Suggested Citation

  • Maja M. Janas & Mark K. Schlegel & Carole E. Harbison & Vedat O. Yilmaz & Yongfeng Jiang & Rubina Parmar & Ivan Zlatev & Adam Castoreno & Huilei Xu & Svetlana Shulga-Morskaya & Kallanthottathil G. Raj, 2018. "Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-02989-4
    DOI: 10.1038/s41467-018-02989-4
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    Cited by:

    1. Megha Subramanian & James McIninch & Ivan Zlatev & Mark K. Schlegel & Charalambos Kaittanis & Tuyen Nguyen & Saket Agarwal & Timothy Racie & Martha Arbaiza Alvarado & Kelly Wassarman & Thomas S. Colli, 2023. "RNAi-mediated rheostat for dynamic control of AAV-delivered transgenes," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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