Locked nucleic acid (LNA) mediated improvements in siRNA stability and functionality.
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.
Elmén
Joacim
J
Center for Genomics and Bioinformatics, Karolinska Institutet 171 77 Stockholm, Sweden. joacim.elmen@cgb.ki.se
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
D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D006801:Humans; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense / Q000737:chemistry*; D016716:PC12 Cells; D034622:RNA Interference; D020871:RNA Stability; D034741:RNA, Small Interfering / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D014709:Vero Cells
D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; C477371:locked nucleic acid