Locked nucleic acid (LNA) mediated improvements in siRNA stability and functionality

Joacim Elmén; Håkan Thonberg; Karl Ljungberg; Miriam Frieden; Majken Westergaard; Yunhe Xu; Britta Wahren; Zicai Liang; Henrik Ørum; Troels Koch; Claes Wahlestedt

doi:10.1093/nar/gki193

Locked nucleic acid (LNA) mediated improvements in siRNA stability and functionality

Joacim Elmén, Håkan Thonberg, Karl Ljungberg, Miriam Frieden, Majken Westergaard, Yunhe Xu, Britta Wahren, Zicai Liang, Henrik Ørum, Troels Koch, Claes Wahlestedt

Research output: Contribution to journal › Article › peer-review

426 Scopus citations

Abstract

Therapeutic application of the recently discovered small interfering RNA (siRNA) gene silencing phenomenon will be dependent on improvements in molecule bio-stability, specificity and delivery. To address these issues, we have systematically modified siRNA with the synthetic RNA-like high affinity nucleotide analogue, Locked Nucleic Acid (LNA). Here, we show that incorporation of LNA substantially enhances serum half-life of siRNA's, which is a key requirement for therapeutic use. Moreover, we provide evidence that LNA is compatible with the intracellular siRNA machinery and can be used to reduce undesired, sequence-related off-target effects. LNA-modified siRNAs targeting the emerging disease SARS, show improved efficiency over unmodified siRNA on certain RNA motifs. The results from this study emphasize LNA's promise in converting siRNA from a functional genomics technology to a therapeutic platform.

Original language	English (US)
Pages (from-to)	439-447
Number of pages	9
Journal	Nucleic acids research
Volume	33
Issue number	1
DOIs	https://doi.org/10.1093/nar/gki193
State	Published - 2005
Externally published	Yes

ASJC Scopus subject areas

Genetics

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Locked nucleic acid (LNA) mediated improvements in siRNA stability and functionality. / Elmén, Joacim; Thonberg, Håkan; Ljungberg, Karl; Frieden, Miriam; Westergaard, Majken; Xu, Yunhe; Wahren, Britta; Liang, Zicai; Ørum, Henrik; Koch, Troels; Wahlestedt, Claes.

In: Nucleic acids research, Vol. 33, No. 1, 2005, p. 439-447.

Research output: Contribution to journal › Article › peer-review

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title = "Locked nucleic acid (LNA) mediated improvements in siRNA stability and functionality",

abstract = "Therapeutic application of the recently discovered small interfering RNA (siRNA) gene silencing phenomenon will be dependent on improvements in molecule bio-stability, specificity and delivery. To address these issues, we have systematically modified siRNA with the synthetic RNA-like high affinity nucleotide analogue, Locked Nucleic Acid (LNA). Here, we show that incorporation of LNA substantially enhances serum half-life of siRNA's, which is a key requirement for therapeutic use. Moreover, we provide evidence that LNA is compatible with the intracellular siRNA machinery and can be used to reduce undesired, sequence-related off-target effects. LNA-modified siRNAs targeting the emerging disease SARS, show improved efficiency over unmodified siRNA on certain RNA motifs. The results from this study emphasize LNA's promise in converting siRNA from a functional genomics technology to a therapeutic platform.",

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note = "Funding Information: This study was supported by the PhD program in biotechnology with an industrial focus and the Foundation for Knowledge and Competence Development, which also provided the funding to pay the Open Access publication charges for this article. Copyright: Copyright 2008 Elsevier B.V., All rights reserved.",

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AU - Elmén, Joacim

AU - Thonberg, Håkan

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AU - Westergaard, Majken

AU - Xu, Yunhe

AU - Wahren, Britta

AU - Liang, Zicai

AU - Ørum, Henrik

AU - Koch, Troels

AU - Wahlestedt, Claes

N1 - Funding Information: This study was supported by the PhD program in biotechnology with an industrial focus and the Foundation for Knowledge and Competence Development, which also provided the funding to pay the Open Access publication charges for this article. Copyright: Copyright 2008 Elsevier B.V., All rights reserved.

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