ArticleMolecular therapy. Nucleic acids2012
Structure Activity Relationships of α-L-LNA Modified Phosphorothioate Gapmer Antisense Oligonucleotides in Animals.
Article in Molecular therapy. Nucleic acids, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 43 citations in OpenAlex.
- Knocking Down Long Noncoding RNAs Using Antisense Oligonucleotide Gapmers.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Regulation of human microglial gene expression and function via RNAase-H active antisense oligonucleotides in vivo in Alzheimer's disease.Molecular neurodegeneration · 2024Article
- Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry.Nature communications · 2023Article
- Nuclease Hydrolysis Does Not Drive the Rapid Signaling Decay of DNA Aptamer-Based Electrochemical Sensors in Biological Fluids.Langmuir : the ACS journal of surfaces and colloids · 2021Article
- Site-specific incorporation of 5'-methyl DNA enhances the therapeutic profile of gapmer ASOs.Nucleic acids research · 2021Article
- Mirror-Image Oligonucleotides: History and Emerging Applications.Chemistry (Weinheim an der Bergstrasse, Germany) · 2019Review
- A Sensitive In Vitro Approach to Assess the Hybridization-Dependent Toxic Potential of High Affinity Gapmer Oligonucleotides.Molecular therapy. Nucleic acids · 2018Article
- Antisense Oligonucleotides Targeting Y-Box Binding Protein-1 Inhibit Tumor Angiogenesis by Downregulating Bcl-xL-VEGFR2/-Tie Axes.Molecular therapy. Nucleic acids · 2017Article
- Oligonucleotide modifications enhance probe stability for single cell transcriptome in vivo analysis (TIVA).Organic & biomolecular chemistry · 2017Article
- Assessing single-stranded oligonucleotide drug-induced effects in vitro reveals key risk factors for thrombocytopenia.PloS one · 2017Article
- Enzymatic separation of epimeric 4-Beilstein journal of organic chemistry · 2017Article
- Development of Antisense Drugs for Dyslipidemia.Journal of atherosclerosis and thrombosis · 2016Review
- Injection site reactions after subcutaneous oligonucleotide therapy.British journal of clinical pharmacology · 2016Review
- Ribonuclease H1-dependent hepatotoxicity caused by locked nucleic acid-modified gapmer antisense oligonucleotides.Scientific reports · 2016Article
- Hepatotoxicity of high affinity gapmer antisense oligonucleotides is mediated by RNase H1 dependent promiscuous reduction of very long pre-mRNA transcripts.Nucleic acids research · 2016Article
- Article
- DNA/RNA heteroduplex oligonucleotide for highly efficient gene silencing.Nature communications · 2015Article
- C5-alkynyl-functionalized α-L-LNA: synthesis, thermal denaturation experiments and enzymatic stability.The Journal of organic chemistry · 2014Article
- Targeting of repeated sequences unique to a gene results in significant increases in antisense oligonucleotide potency.PloS one · 2014Article
- Defining the factors that contribute to on-target specificity of antisense oligonucleotides.PloS one · 2014Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We report the structure activity relationships of short 14-mer phosphorothioate gapmer antisense oligonucleotides (ASOs) modified with α-L-locked nucleic acid (LNA) and related modifications targeting phosphatase and tensin homologue (PTEN) messenger RNA in mice. α-L-LNA represents the α-anomer of enantio-LNA and modified oligonucleotides show LNA like binding affinity for complementary RNA. In contrast to sequence matched LNA gapmer ASOs which showed elevations in plasma alanine aminotransferase (ALT) levels indicative of hepatotoxicity, gapmer ASOs modified with α-L-LNA and related analogs in the flanks showed potent downregulation of PTEN messenger RNA in liver tissue without producing elevations in plasma ALT levels. However, the α-L-LNA ASO showed a moderate dose-dependent increase in liver and spleen weights suggesting a higher propensity for immune stimulation. Interestingly, replacing α-L-LNA nucleotides in the 3'- and 5'-flanks with R-5'-Me-α-L-LNA but not R-6'-Me- or 3'-Me-α-L-LNA nucleotides, reversed the drug induced increase in organ weights. Examination of structural models of dinucleotide units suggested that the 5'-Me group increases steric bulk in close proximity to the phosphorothioate backbone or produces subtle changes in the backbone conformation which could interfere with recognition of the ASO by putative immune receptors. Our data suggests that introducing steric bulk at the 5'-position of the sugar-phosphate backbone could be a general strategy to mitigate the immunostimulatory profile of oligonucleotide drugs. In a clinical setting, proinflammatory effects manifest themselves as injection site reactions and flu-like symptoms. Thus, a mitigation of these effects could increase patient comfort and compliance when treated with ASOs.Molecular Therapy - Nucleic Acids (2012) 1, e47; doi:10.1038/mtna.2012.34; published online 18 September 2012.
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Registered trials
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