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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.

SUBMITTER: Elmen J 

PROVIDER: S-EPMC546170 | biostudies-literature | 2005

REPOSITORIES: biostudies-literature

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

Elmén Joacim J   Thonberg Håkan H   Ljungberg Karl K   Frieden Miriam M   Westergaard Majken M   Xu Yunhe Y   Wahren Britta B   Liang Zicai Z   Ørum Henrik H   Koch Troels T   Wahlestedt Claes C  

Nucleic acids research 20050114 1

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 p  ...[more]

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