Silencing of microRNA families by seed-targeting tiny LNAs

By S. Obad, Camila O. dos Santos, A. Petri, M. Heidenblad, O. Broom, C. Ruse, Cexiong Fu, M. Lindow, J. Stenvang, E. Straarup and 5 more. Nature Genetics, 2011

641 citations recorded by the source corpus.

The challenge of understanding the widespread biological roles of animal microRNAs (miRNAs) has prompted the development of genetic and functional genomics technologies for miRNA loss-of-function studies. However, tools for exploring the functions of entire miRNA families are still limited. We developed a method that enables antagonism of miRNA function using seed-targeting 8-mer locked nucleic acid (LNA) oligonucleotides, termed tiny LNAs. Transfection of tiny LNAs into cells resulted in simultaneous inhibition of miRNAs within families sharing the same seed with concomitant upregulation of direct targets. In addition, systemically delivered, unconjugated tiny LNAs showed uptake in many normal tissues and in breast tumors in mice, coinciding with long-term miRNA silencing. Transcriptional and proteomic profiling suggested that tiny LNAs have negligible off-target effects, not significantly altering the output from mRNAs with perfect tiny LNA complementary sites. Considered together, these data support the utility of tiny LNAs in elucidating the functions of miRNA families in vivo.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/0985d68fdeba7c655e2420072ee511d42d458fe9

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Citations in the corpus

MicroRNAs in stress signaling and human disease (2012, background): “Because of the high affinity of LNA-modified antisense oligonucleotides for their targets, it has been possible to use short, so-called ‘‘tiny’’ LNAs, to target just the seed regions of miRNAs, thereby allowing for inhibition of miRNA families that share homology in this region (Hullinger et al., 20”
In vivo delivery of miRNAs for cancer therapy: Challenges and strategies (2014, background): “Systemic delivery of anti-miR-21 tiny LNA showed significant repression of the miR-21 luciferase reporter in orthotopic breast tumors [106].”
Non-coding RNAs in Development and Disease: Background, Mechanisms, and Therapeutic Approaches. (2016, background): “This leads to a higher efficiency and makes it possible to use shorter sequences to target the miRNA’s seed sequence (“tiny LNA”) (67, 205, 212).”
Development of microRNA therapeutics is coming of age (2014, positive): “…and pharmacological activity have also been reported in other peripheral tissues, such as heart, lung, spleen and bone marrow (Elme´n et al , 2008a,b; Worm et al , 2009; Obad et al , 2011; Hildebrandt-Eriksen et al , 2012; Hullinger et al , 2012; Ranganathan et al , 2012; Zhang et al , 2012).”
Therapeutic Inhibition of miR-208a Improves Cardiac Function and Survival During Heart Failure (2011, neutral): “28 We have tested additional lengths of anti-miRs; however, the 16-mer used here was the most efficacious in cardiac inhibition (data not shown).”