Effective RNAi-mediated gene silencing without interruption of the endogenous microRNA pathway

Matthias John, Rainer Constien, Akin Akinc, Michael Goldberg, Young Ah Moon, Martina Spranger, Philipp Hadwiger, Jürgen Soutschek, Hans Peter Vornlocher, Muthiah Manoharan, Markus Stoffel, Robert Langer, Daniel G. Anderson, Jay D. Horton, Victor Koteliansky, David Bumcrot

Research output: Contribution to journalArticle

128 Citations (Scopus)

Abstract

Systemic administration of synthetic small interfering RNAs (siRNAs) effectively silences hepatocyte gene expression in rodents and primates. Whether or not in vivo gene silencing by synthetic siRNA can disrupt the endogenous microRNA (miRNA) pathway remains to be addressed. Here we show that effective target-gene silencing in the mouse and hamster liver can be achieved by systemic administration of synthetic siRNA without any demonstrable effect on miRNA levels or activity. Indeed, siRNA targeting two hepatocyte-specific genes (apolipoprotein B and factor VII) that achieved efficient (∼80%) silencing of messenger RNA transcripts and a third irrelevant siRNA control were administered to mice without significant changes in the levels of three hepatocyte-expressed miRNAs (miR-122, miR-16 and let-7a) or an effect on miRNA activity. Moreover, multiple administrations of an siRNA targeting the hepatocyte-expressed gene Scap in hamsters achieved long-term mRNA silencing without significant changes in miR-122 levels. This study advances the use of siRNAs as safe and effective tools to silence gene transcripts in animal studies, and supports the continued advancement of RNA interference therapeutics using synthetic siRNA.

Original languageEnglish (US)
Pages (from-to)745-747
Number of pages3
JournalNature
Volume449
Issue number7163
DOIs
StatePublished - Oct 11 2007

Fingerprint

Gene Silencing
RNA Interference
MicroRNAs
Small Interfering RNA
Hepatocytes
Cricetinae
Genes
Messenger RNA
Factor VII
Apolipoproteins B
Primates
Rodentia
Gene Expression
Liver

ASJC Scopus subject areas

  • General

Cite this

John, M., Constien, R., Akinc, A., Goldberg, M., Moon, Y. A., Spranger, M., ... Bumcrot, D. (2007). Effective RNAi-mediated gene silencing without interruption of the endogenous microRNA pathway. Nature, 449(7163), 745-747. https://doi.org/10.1038/nature06179

Effective RNAi-mediated gene silencing without interruption of the endogenous microRNA pathway. / John, Matthias; Constien, Rainer; Akinc, Akin; Goldberg, Michael; Moon, Young Ah; Spranger, Martina; Hadwiger, Philipp; Soutschek, Jürgen; Vornlocher, Hans Peter; Manoharan, Muthiah; Stoffel, Markus; Langer, Robert; Anderson, Daniel G.; Horton, Jay D.; Koteliansky, Victor; Bumcrot, David.

In: Nature, Vol. 449, No. 7163, 11.10.2007, p. 745-747.

Research output: Contribution to journalArticle

John, M, Constien, R, Akinc, A, Goldberg, M, Moon, YA, Spranger, M, Hadwiger, P, Soutschek, J, Vornlocher, HP, Manoharan, M, Stoffel, M, Langer, R, Anderson, DG, Horton, JD, Koteliansky, V & Bumcrot, D 2007, 'Effective RNAi-mediated gene silencing without interruption of the endogenous microRNA pathway', Nature, vol. 449, no. 7163, pp. 745-747. https://doi.org/10.1038/nature06179
John M, Constien R, Akinc A, Goldberg M, Moon YA, Spranger M et al. Effective RNAi-mediated gene silencing without interruption of the endogenous microRNA pathway. Nature. 2007 Oct 11;449(7163):745-747. https://doi.org/10.1038/nature06179
John, Matthias ; Constien, Rainer ; Akinc, Akin ; Goldberg, Michael ; Moon, Young Ah ; Spranger, Martina ; Hadwiger, Philipp ; Soutschek, Jürgen ; Vornlocher, Hans Peter ; Manoharan, Muthiah ; Stoffel, Markus ; Langer, Robert ; Anderson, Daniel G. ; Horton, Jay D. ; Koteliansky, Victor ; Bumcrot, David. / Effective RNAi-mediated gene silencing without interruption of the endogenous microRNA pathway. In: Nature. 2007 ; Vol. 449, No. 7163. pp. 745-747.
@article{b5d9a78da9234de18fc2ebe7ef234f0e,
title = "Effective RNAi-mediated gene silencing without interruption of the endogenous microRNA pathway",
abstract = "Systemic administration of synthetic small interfering RNAs (siRNAs) effectively silences hepatocyte gene expression in rodents and primates. Whether or not in vivo gene silencing by synthetic siRNA can disrupt the endogenous microRNA (miRNA) pathway remains to be addressed. Here we show that effective target-gene silencing in the mouse and hamster liver can be achieved by systemic administration of synthetic siRNA without any demonstrable effect on miRNA levels or activity. Indeed, siRNA targeting two hepatocyte-specific genes (apolipoprotein B and factor VII) that achieved efficient (∼80{\%}) silencing of messenger RNA transcripts and a third irrelevant siRNA control were administered to mice without significant changes in the levels of three hepatocyte-expressed miRNAs (miR-122, miR-16 and let-7a) or an effect on miRNA activity. Moreover, multiple administrations of an siRNA targeting the hepatocyte-expressed gene Scap in hamsters achieved long-term mRNA silencing without significant changes in miR-122 levels. This study advances the use of siRNAs as safe and effective tools to silence gene transcripts in animal studies, and supports the continued advancement of RNA interference therapeutics using synthetic siRNA.",
author = "Matthias John and Rainer Constien and Akin Akinc and Michael Goldberg and Moon, {Young Ah} and Martina Spranger and Philipp Hadwiger and J{\"u}rgen Soutschek and Vornlocher, {Hans Peter} and Muthiah Manoharan and Markus Stoffel and Robert Langer and Anderson, {Daniel G.} and Horton, {Jay D.} and Victor Koteliansky and David Bumcrot",
year = "2007",
month = "10",
day = "11",
doi = "10.1038/nature06179",
language = "English (US)",
volume = "449",
pages = "745--747",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7163",

}

TY - JOUR

T1 - Effective RNAi-mediated gene silencing without interruption of the endogenous microRNA pathway

AU - John, Matthias

AU - Constien, Rainer

AU - Akinc, Akin

AU - Goldberg, Michael

AU - Moon, Young Ah

AU - Spranger, Martina

AU - Hadwiger, Philipp

AU - Soutschek, Jürgen

AU - Vornlocher, Hans Peter

AU - Manoharan, Muthiah

AU - Stoffel, Markus

AU - Langer, Robert

AU - Anderson, Daniel G.

AU - Horton, Jay D.

AU - Koteliansky, Victor

AU - Bumcrot, David

PY - 2007/10/11

Y1 - 2007/10/11

N2 - Systemic administration of synthetic small interfering RNAs (siRNAs) effectively silences hepatocyte gene expression in rodents and primates. Whether or not in vivo gene silencing by synthetic siRNA can disrupt the endogenous microRNA (miRNA) pathway remains to be addressed. Here we show that effective target-gene silencing in the mouse and hamster liver can be achieved by systemic administration of synthetic siRNA without any demonstrable effect on miRNA levels or activity. Indeed, siRNA targeting two hepatocyte-specific genes (apolipoprotein B and factor VII) that achieved efficient (∼80%) silencing of messenger RNA transcripts and a third irrelevant siRNA control were administered to mice without significant changes in the levels of three hepatocyte-expressed miRNAs (miR-122, miR-16 and let-7a) or an effect on miRNA activity. Moreover, multiple administrations of an siRNA targeting the hepatocyte-expressed gene Scap in hamsters achieved long-term mRNA silencing without significant changes in miR-122 levels. This study advances the use of siRNAs as safe and effective tools to silence gene transcripts in animal studies, and supports the continued advancement of RNA interference therapeutics using synthetic siRNA.

AB - Systemic administration of synthetic small interfering RNAs (siRNAs) effectively silences hepatocyte gene expression in rodents and primates. Whether or not in vivo gene silencing by synthetic siRNA can disrupt the endogenous microRNA (miRNA) pathway remains to be addressed. Here we show that effective target-gene silencing in the mouse and hamster liver can be achieved by systemic administration of synthetic siRNA without any demonstrable effect on miRNA levels or activity. Indeed, siRNA targeting two hepatocyte-specific genes (apolipoprotein B and factor VII) that achieved efficient (∼80%) silencing of messenger RNA transcripts and a third irrelevant siRNA control were administered to mice without significant changes in the levels of three hepatocyte-expressed miRNAs (miR-122, miR-16 and let-7a) or an effect on miRNA activity. Moreover, multiple administrations of an siRNA targeting the hepatocyte-expressed gene Scap in hamsters achieved long-term mRNA silencing without significant changes in miR-122 levels. This study advances the use of siRNAs as safe and effective tools to silence gene transcripts in animal studies, and supports the continued advancement of RNA interference therapeutics using synthetic siRNA.

UR - http://www.scopus.com/inward/record.url?scp=35148845281&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=35148845281&partnerID=8YFLogxK

U2 - 10.1038/nature06179

DO - 10.1038/nature06179

M3 - Article

VL - 449

SP - 745

EP - 747

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7163

ER -