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Molecular Pharmacology

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Research ArticleArticle

RNA-Induced Silencing Complex-Bound Small Interfering RNA Is a Determinant of RNA Interference-Mediated Gene Silencing in Mice

Jie Wei, Jeffrey Jones, Jing Kang, Ananda Card, Michael Krimm, Paula Hancock, Yi Pei, Brandon Ason, Elmer Payson, Natalya Dubinina, Mark Cancilla, Mark Stroh, Julja Burchard, Alan B. Sachs, Jerome H. Hochman, W. Michael Flanagan and Nelly A. Kuklin
Molecular Pharmacology June 2011, 79 (6) 953-963; DOI: https://doi.org/10.1124/mol.110.070409
Jie Wei
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Jeffrey Jones
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Jing Kang
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Ananda Card
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Michael Krimm
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Paula Hancock
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Yi Pei
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Brandon Ason
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Elmer Payson
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Natalya Dubinina
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Mark Cancilla
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Mark Stroh
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Julja Burchard
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Alan B. Sachs
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Jerome H. Hochman
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Abstract

Deeper knowledge of pharmacokinetic and pharmacodynamic (PK/PD) concepts for RNA therapeutics is important to streamline the drug development process and for rigorous selection of best performing drug candidates. Here we characterized the PK/PD relationship for small interfering RNAs (siRNAs) targeting luciferase by examining siRNA concentration in plasma and liver, the temporal RNA-induced silencing complex binding profiles, mRNA reduction, and protein inhibition measured by noninvasive bioluminescent imaging. A dose-dependent and time-related decrease in bioluminescence was detected over 25 days after a single treatment of a lipid nanoparticle-formulated siRNA targeting luciferase messenger RNA. A direct relationship was observed between the degree of in vivo mRNA and protein reduction and the Argonaute2 (Ago2)-bound siRNA fraction but not with the total amount of siRNA found in the liver, suggesting that the Ago2-siRNA complex is the key determinant of target inhibition. These observations were confirmed for an additional siRNA that targets endogenously expressed Sjögren syndrome antigen B (Ssb) mRNA, indicating that our observations are not limited to a transgenic mouse system. Our data provide detailed information of the temporal regulation of siRNA liver delivery, Ago2 loading, mRNA reduction, and protein inhibition that are essential for the rapid and cost-effective clinical development of siRNAs therapeutics.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by Merck and Co., Inc.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.070409.

  • ABBREVIATIONS:

    RNAi
    RNA interference
    siRNA
    small interfering RNA
    PK
    pharmacokinetic
    PD
    pharmacodynamic
    RISC
    RNA-induced silencing complex
    RSV
    respiratory syncytial virus
    LNP
    lipid nanoparticle
    CMV
    cytomegalovirus
    AUC
    area under the curve
    RT-PCR
    reverse transcription-polymerase chain reaction
    qPCR
    quantitative PCR
    GAPDH
    glyceraldehyde 3-phosphate dehydrogenase
    UC3
    scrambled universal control
    PBS
    phosphate-buffered saline
    Ago2
    Argonaute2
    Luc
    Luciferase
    Ssb
    Sjögren syndrome antigen B
    MGBNFQ
    minor groove binder nonfluorescent quencher.

  • Received December 7, 2010.
  • Accepted March 21, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (6)
Molecular Pharmacology
Vol. 79, Issue 6
1 Jun 2011
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Research ArticleArticle

RNA-Induced Silencing Complex-Bound Small Interfering RNA Is a Determinant of RNA Interference-Mediated Gene Silencing in Mice

Jie Wei, Jeffrey Jones, Jing Kang, Ananda Card, Michael Krimm, Paula Hancock, Yi Pei, Brandon Ason, Elmer Payson, Natalya Dubinina, Mark Cancilla, Mark Stroh, Julja Burchard, Alan B. Sachs, Jerome H. Hochman, W. Michael Flanagan and Nelly A. Kuklin
Molecular Pharmacology June 1, 2011, 79 (6) 953-963; DOI: https://doi.org/10.1124/mol.110.070409

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Research ArticleArticle

RNA-Induced Silencing Complex-Bound Small Interfering RNA Is a Determinant of RNA Interference-Mediated Gene Silencing in Mice

Jie Wei, Jeffrey Jones, Jing Kang, Ananda Card, Michael Krimm, Paula Hancock, Yi Pei, Brandon Ason, Elmer Payson, Natalya Dubinina, Mark Cancilla, Mark Stroh, Julja Burchard, Alan B. Sachs, Jerome H. Hochman, W. Michael Flanagan and Nelly A. Kuklin
Molecular Pharmacology June 1, 2011, 79 (6) 953-963; DOI: https://doi.org/10.1124/mol.110.070409
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