Nature Communications (Feb 2018)

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

  • 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. Rajeev,
  • Muthiah Manoharan,
  • Natalie D. Keirstead,
  • Martin A. Maier,
  • Vasant Jadhav

DOI
https://doi.org/10.1038/s41467-018-02989-4
Journal volume & issue
Vol. 9, no. 1
pp. 1 – 10

Abstract

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A subset of chemically-modified siRNAs conjugated to trivalent GalNAc may fail during nonclinical development due to rat hepatotoxicity. Here, the authors show that hepatotoxicity may be accounted for by microRNA-like off-target effects of siRNA and can be mitigated by a thermally destabilizing modification in the siRNA seed region.