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

• Published in: Nucleic acids research Vol. 33; no. 1; pp. 439 - 447
• Main Authors: Elmén, Joacim, Thonberg, Håkan, Ljungberg, Karl, Frieden, Miriam, Westergaard, Majken, Xu, Yunhe, Wahren, Britta, Liang, Zicai, Ørum, Henrik, Koch, Troels, Wahlestedt, Claes
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-01-2005; Oxford Publishing Limited (England)
• Subjects: Animals; Cell Line; Cercopithecus aethiops; Humans; Medicin och hälsovetenskap; Oligonucleotides; Oligonucleotides, Antisense - chemistry; PC12 Cells; Rats; RNA Interference; RNA Stability; RNA, Small Interfering - blood; RNA, Small Interfering - chemistry; RNA, Small Interfering - pharmacology; Vero Cells
• ISSN: 0305-1048; 1362-4962; 1362-4962
• DOI: 10.1093/nar/gki193

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.