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Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways

Author

Listed:
  • Dirk Grimm

    (Stanford University, School of Medicine)

  • Konrad L. Streetz

    (Stanford University, School of Medicine
    University-Hospital Aachen)

  • Catherine L. Jopling

    (Department of Microbiology and Immunology)

  • Theresa A. Storm

    (Stanford University, School of Medicine)

  • Kusum Pandey

    (Stanford University, School of Medicine)

  • Corrine R. Davis

    (Department of Comparative Medicine)

  • Patricia Marion

    (Hepadnavirus Testing, Inc.)

  • Felix Salazar

    (Hepadnavirus Testing, Inc.)

  • Mark A. Kay

    (Stanford University, School of Medicine)

Abstract

Adverse reaction to shRNA It's early days, but RNA interference (RNAi) is already seen as a potentially important therapeutic technique for silencing genes. One way of delivering short interfering RNAs (siRNAs) in vivo involves cloning the siRNA sequence as a short hairpin into an adenovirus vector. When introduced into the animal, the hairpin sequence is expressed, forms a duplex RNA (shRNA), and is processed by the RNAi pathway. A study of the long-term effects of shRNA expression in the livers of adult mice strikes a note of caution, however. It turns out that many shRNAs are toxic when expressed in mice. The toxicity — often fatal — seems to result from competition between shRNAs and endogenous microRNAs for binding to exportin-5, a factor involved in transporting molecules out of the nucleus. There is growing interest in developing shRNA-based therapies, and until now there has been little evidence to suggest severe in vivo toxicity.

Suggested Citation

  • Dirk Grimm & Konrad L. Streetz & Catherine L. Jopling & Theresa A. Storm & Kusum Pandey & Corrine R. Davis & Patricia Marion & Felix Salazar & Mark A. Kay, 2006. "Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways," Nature, Nature, vol. 441(7092), pages 537-541, May.
    • Handle: RePEc:nat:nature:v:441:y:2006:i:7092:d:10.1038_nature04791
    DOI: 10.1038/nature04791
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    Cited by:

    1. Perla Pucci & Liam C. Lee & Miaojun Han & Jamie D. Matthews & Leila Jahangiri & Michaela Schlederer & Eleanor Manners & Annabel Sorby-Adams & Joshua Kaggie & Ricky M. Trigg & Christopher Steel & Lucy , 2024. "Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Yu Zhou & Peike Sheng & Jiayi Li & Yudan Li & Mingyi Xie & Alexander A. Green, 2024. "Conditional RNA interference in mammalian cells via RNA transactivation," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    3. Xiaolong Cheng & Zexu Li & Ruocheng Shan & Zihan Li & Shengnan Wang & Wenchang Zhao & Han Zhang & Lumen Chao & Jian Peng & Teng Fei & Wei Li, 2023. "Modeling CRISPR-Cas13d on-target and off-target effects using machine learning approaches," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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