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.
authors.affiliation: Center for Genomics and Bioinformatics, Karolinska Institutet 171 77 Stockholm, Sweden. joacim.elmen@cgb.ki.se
authors.forename: Joacim
authors.initials: J
authors.lastname: Elmén
authors.forename: Håkan
authors.initials: H
authors.lastname: Thonberg
authors.forename: Karl
authors.initials: K
authors.lastname: Ljungberg
authors.forename: Miriam
authors.initials: M
authors.lastname: Frieden
authors.forename: Majken
authors.initials: M
authors.lastname: Westergaard
authors.forename: Yunhe
authors.initials: Y
authors.lastname: Xu
authors.forename: Britta
authors.initials: B
authors.lastname: Wahren
authors.forename: Zicai
authors.initials: Z
authors.lastname: Liang
authors.forename: Henrik
authors.initials: H
authors.lastname: Ørum
authors.forename: Troels
authors.initials: T
authors.lastname: Koch
authors.forename: Claes
authors.initials: C
authors.lastname: Wahlestedt
mesh_terms: 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
chemical_list: D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; C477371:locked nucleic acid