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. 2016;3(4):e1393.
doi: 10.14800/rd.1393. Epub 2016 Aug 15.

Antisense Oligonucleotides: Treatment Strategies and Cellular Internalization

Colton M Miller  1 , Edward N Harris  1
Affiliations

Antisense Oligonucleotides: Treatment Strategies and Cellular Internalization

Colton M Miller et al. RNA Dis. 2016.

Abstract

The clinical applicaton of antisense oligonucleotides (ASOs) is becoming more of a reality as several drugs have been approved for the treatment of human disorders and many others are in various phases in development and clinical trials. ASOs are short DNA/RNA oligos which are heavily modified to increase their stability in biological fluids and retain the properties of creating RNA-RNA and DNA-RNA duplexes that knock-down or correct genetic expression. This review outlines several strategies that ASOs utilize for the treatment of various congenital diseases and syndromes that develop with aging. In addition, we discuss some of the mechanisms for specific non-targeted ASO internalization within cells.

Keywords: Stabilin; antisense oligonucleotide; clearance; endocytosis; phosphorothioate; splicing.

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Figures

Figure 1
Figure 1. RNase H mediated destruction of targeted mRNA
ASOs are internalized in the cells by several mechanisms (clathrin/caveolin-mediated endocytosis, micropinocytosis, etc.) in which a small subset of the ASOs escape into the cytoplasm and/or nucleus. Hybridization of the ASO with complementary hnRNA or mRNA induces RNase H cleavage of the RNA while leaving the ASO intact for subsequent hybridizations.
Figure 2
Figure 2. Backbone structures of ASO modifications
A. Unmodified phosphodiester backbone. B. Generation 1 phosphorothioate (PS-ASO) modification. C. Generation 2 2′-methoxyethyl phosphorothioate (2′ MOE-PS-ASO) modification.
Figure 3
Figure 3. Exon skipping as a mechanism for “gene” correction
A. The ASO mechanism for the treatment of Duchenne’s Muscular Dystrophy (DMD) in which the ASO binds to exon 51 containing the mutation and force skips the exon in transcription producing a slightly shorter but active gene product. B. In cases of Spinal Muscular Atrophy (SMA), heterogenous nuclear ribonuclear proteins (hnRNPs) bind to exon 7 and prevent further hnRNA modification and subsequent translation. C. SMA treatment with a 2′-methoxyethyl (2′-MOE) modified ASO (ASO-10-27) displaces hnRNPs and allows translation of the full-length gene product. D. SMA treatment with a 2′-Fluoro (2′-F) modified ASO recruits Interleukin Enhancer 2 and 3 proteins which displace hnRNPs and allow for the translation of a shorter mRNA producing a smaller protein product that is still partially active. Figure adapted and modified from Aartsma-Rus et al. [23] and Rigo et al. [35]
See this image and copyright information in PMC

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References

    1. Wu H, Lima WF, Crooke ST. Properties of Cloned and Expressed Human RNase H1. J Biol Chem. 1999;274:28270–8. - PubMed
    1. Bennett CF, Swayze EE. RNA Targeting Therapeutics: Molecular Mechanisms of Antisense Oligonucleotides as a Therapeutic Platform. Annu Rev Pharmacol Toxicol. 2010;50:259–93. - PubMed
    1. Eckstein F. Phosphorothioates, Essential Components of Therapeutic Oligonucleotides. Nucleic Acid Ther. 2014;24:374–87. - PubMed
    1. Beltinger C, Saragovi HU, Smith RM, LeSauteur L, Shah N, DeDionisio L, et al. Binding, uptake, and intracellular trafficking of phosphorothioate-modified oligodeoxynucleotides. J Clin Invest. 1995;95:1814–23. - PMC - PubMed
    1. Bijsterbosch MK, Manoharan M, Rump ET, De Vrueh RLA, van Veghel R, Tivel KL, et al. In vivo fate of phosphorothioate antisense oligodeoxynucleotides: predominant uptake by scavenger receptors on endothelial liver cells. Nucleic Acids Res. 1997;25:3290–6. - PMC - PubMed

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