Adenosine Modification May Be Preferred for Reducing siRNA Immune Stimulation

被引：20

作者：

Fucini, Raymond V. ^{[1
]}

Haringsma, Henry J. ^{[1
]}

Deng, Patricia ^{[1
]}

Flanagan, W. Michael ^{[1
]}

Willingham, Aarron T. ^{[1
]}

机构：

[1] Sirna Therapeut, San Francisco, CA USA

来源：

NUCLEIC ACID THERAPEUTICS | 2012年 / 22卷 / 03期

关键词：

SMALL INTERFERING RNA; IN-VIVO; CHEMICAL-MODIFICATION; SYNTHETIC SIRNA; POTENT; CELLS; IMMUNOSTIMULATION; VITRO; TLR7;

D O I：

10.1089/nat.2011.0334

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The immune stimulation induced by short interfering RNAs (siRNAs) has been reported to be quieted or abrogated by methoxy or fluoro modifications of the 2' position of the ribose sugar. However, variables such as the type of modification, nucleotide preference, and strand bias have not been systematically evaluated. Here, we report the results of a screen of several modified siRNAs via a human peripheral blood monocyte cytokine induction assay. Unlike corresponding modifications of guanosine, cytidine, or uridine, 2'-fluoro modification of adenosine significantly reduced cytokine induction while retaining siRNA knockdown activity. The results of this study suggest adenosine as an optimal target for modification.

引用

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页码：205 / 210

页数：6

相关论文

共 21 条

[1] Evaluation of Efficacy, Biodistribution, and Inflammation for a Potent siRNA Nanoparticle: Effect of Dexamethasone Co-treatment [J].

Abrams, Marc T. ;

Koser, Martin L. ;

Seitzer, Jessica ;

Williams, Stephanie C. ;

DiPietro, Martha A. ;

Wang, Weimin ;

Shaw, Andrew W. ;

Mao, Xianzhi ;

Jadhav, Vasant ;

Davide, Joseph P. ;

Burke, Paul A. ;

Sachs, Alan B. ;

Stirdivant, Steven M. ;

Sepp-Lorenzino, Laura .

MOLECULAR THERAPY, 2010, 18 (01) :171-180

[2] Fully 2′-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA [J].

Allerson, CR ;

Sioufi, N ;

Jarres, R ;

Prakash, TP ;

Naik, N ;

Berdeja, A ;

Wanders, L ;

Griffey, RH ;

Swayze, EE ;

Bhat, B .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (04) :901-904

[3] Chemical Modification of siRNAs for In Vivo Use [J].

Behlke, Mark A. .

OLIGONUCLEOTIDES, 2008, 18 (04) :305-319

[4]

Bramsen JB, 2011, METHODS MOL BIOL, V721, P77, DOI 10.1007/978-1-61779-037-9_5

[5] Gene expression analysis in blood cells in response to unmodified and 2′-modified siRNAs reveals TLR-dependent and independent effects [J].

Cekaite, Lina ;

Furset, Gro ;

Hovig, Eivind ;

Sioud, Mouldy .

JOURNAL OF MOLECULAR BIOLOGY, 2007, 365 (01) :90-108

[6] siRNA function in RNAi: A chemical modification analysis [J].

Chiu, YL ;

Rana, TM .

RNA, 2003, 9 (09) :1034-1048

[7] Modifications in small interfering RNA that separate immunostimulation from RNA interference [J].

Eberle, Florian ;

Giessler, Kerstin ;

Deck, Christopher ;

Heeg, Klaus ;

Peter, Mirjam ;

Richert, Clemens ;

Dalpke, Alexander H. .

JOURNAL OF IMMUNOLOGY, 2008, 180 (05) :3229-3237

[8] Sequence-specific potent induction of IFN-α by short interfering RNA in plasmacytoid dendritic cells through TLR7 [J].

Hornung, V ;

Guenthner-Biller, M ;

Bourquin, C ;

Ablasser, A ;

Schlee, M ;

Uematsu, S ;

Noronha, A ;

Manoharan, M ;

Akira, S ;

de Fougerolles, A ;

Endres, S ;

Hartmann, G .

NATURE MEDICINE, 2005, 11 (03) :263-270

[9] Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA [J].

Judge, AD ;

Sood, V ;

Shaw, JR ;

Fang, D ;

McClintock, K ;

MacLachlan, I .

NATURE BIOTECHNOLOGY, 2005, 23 (04) :457-462

[10] Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo [J].

Judge, AD ;

Bola, G ;

Lee, ACH ;

MacLachlan, I .

MOLECULAR THERAPY, 2006, 13 (03) :494-505