Potent inhibition of microRNA in vivo without degradation

被引：159

作者：

Davis, Scott ^{[1
]}

Propp, Stephanie ^{[2
]}

Freier, Susan M. ^{[2
]}

Jones, Laura E. ^{[3
]}

Serra, Martin J. ^{[3
]}

Kinberger, Garth ^{[2
]}

Bhat, Balkrishen ^{[1
]}

Swayze, Eric E. ^{[2
]}

Bennett, C. Frank ^{[2
]}

Esau, Christine ^{[1
]}

机构：

[1] Regulus Therapeut, Carlsbad, CA 92008 USA

[2] Isis Pharmaceut, Carlsbad, CA 92008 USA

[3] Allegheny Coll, Meadville, PA 16335 USA

来源：

NUCLEIC ACIDS RESEARCH | 2009年 / 37卷 / 01期

基金：

美国国家卫生研究院;

关键词：

ANTISENSE OLIGONUCLEOTIDES; BIOGENESIS; MICE;

D O I：

10.1093/nar/gkn904

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Chemically modified antisense oligonucleotides (ASOs) are widely used as a tool to functionalize microRNAs (miRNAs). Reduction of miRNA level after ASO inhibition is commonly reported to show efficacy. Whether this is the most relevant endpoint for measuring miRNA inhibition has not been adequately addressed in the field although it has important implications for evaluating miRNA targeting studies. Using a novel approach to quantitate miRNA levels in the presence of excess ASO, we have discovered that the outcome of miRNA inhibition can vary depending on the chemical modification of the ASO. Although some miRNA inhibitors cause a decrease in mature miRNA levels, we have identified a novel 2-fluoro/2-methoxyethyl modified ASO motif with dramatically improved in vivo potency which does not. These studies show there are multiple mechanisms of miRNA inhibition by ASOs and that evaluation of secondary endpoints is crucial for interpreting miRNA inhibition studies.

引用

页码：70 / 77

页数：8

共 23 条

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