TY - JOUR
T1 - Utilization of unlocked nucleic acid (UNA) to enhance siRNA performance in vitro and in vivo
AU - Laursen, Maria B.
AU - Pakula, Malgorzata M.
AU - Gao, Shan
AU - Fluiter, Kees
AU - Mook, Olaf R.
AU - Baas, Frank
AU - Langklær, Niels
AU - Wengel, Suzy L.
AU - Wengel, Jesper
AU - Kjems, Jørgen
AU - Bramsen, Jesper B.
PY - 2010
Y1 - 2010
N2 - Small interfering RNAs (siRNAs) are now established as a favourite tool to reduce gene expression by RNA interference (RNAi) in mammalian cell culture. However, limitations in potency, duration, delivery and specificity of the gene knockdown (KD) are still major obstacles that need further addressing. Recent studies have successfully improved siRNA performance by the introduction of several types of chemical modifications. Here we explore the effect of incorporating unlocked nucleic acid (UNA) into siRNA designs. The acyclic UNA monomers lack the C2'-C3'-bond of the RNA ribose ring and additively decrease nucleic acid duplex thermostability. We show that UNA-modifications of siRNAs are compatible with efficient RNAi and can improve siRNA performance both in vitro and in vivo. In particular, we find that the destabilizing properties of UNA are well suited to enhance the potency of siRNAs which are heavily modified by other chemical modifications such as locked nucleic acid (LNA), C4'hydroxymethyl-DNA (HM), 2'-O-methyl-RNA (OMe), DNA and 2'-Flouro-DNA (F). Interestingly, we find that naked, but UNA-modified siRNAs have dramatically increased biostability in mice and can induce potent KD in a xenograft model of human pancreas cancer. Hereby UNA constitutes an important type of chemical modification for future siRNA designs
AB - Small interfering RNAs (siRNAs) are now established as a favourite tool to reduce gene expression by RNA interference (RNAi) in mammalian cell culture. However, limitations in potency, duration, delivery and specificity of the gene knockdown (KD) are still major obstacles that need further addressing. Recent studies have successfully improved siRNA performance by the introduction of several types of chemical modifications. Here we explore the effect of incorporating unlocked nucleic acid (UNA) into siRNA designs. The acyclic UNA monomers lack the C2'-C3'-bond of the RNA ribose ring and additively decrease nucleic acid duplex thermostability. We show that UNA-modifications of siRNAs are compatible with efficient RNAi and can improve siRNA performance both in vitro and in vivo. In particular, we find that the destabilizing properties of UNA are well suited to enhance the potency of siRNAs which are heavily modified by other chemical modifications such as locked nucleic acid (LNA), C4'hydroxymethyl-DNA (HM), 2'-O-methyl-RNA (OMe), DNA and 2'-Flouro-DNA (F). Interestingly, we find that naked, but UNA-modified siRNAs have dramatically increased biostability in mice and can induce potent KD in a xenograft model of human pancreas cancer. Hereby UNA constitutes an important type of chemical modification for future siRNA designs
U2 - https://doi.org/10.1039/b918869j
DO - https://doi.org/10.1039/b918869j
M3 - Article
C2 - 20567772
SN - 1742-206X
VL - 6
SP - 862
EP - 870
JO - Molecular bioSystems
JF - Molecular bioSystems
IS - 5
ER -