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.

Highlights

  • One of the growing fields of interest pertaining to nucleic acid-based gene silencing/modification is the application of antisense oligonucleotides (ASOs)

  • Duchenne’s muscular dystrophy (DMD) is a rare but debilitating X-linked disease causing muscle wasting by mutations arising from the DMD gene, which codes for dystrophin

  • Previous work that has looked at these proteins as well as many other heparin binding proteins, such as lamelin and fibronectin have been identified has poteintal targets for ASO binding based on the role of ASOs binding to the extra-cellular matrix (ECM), as well as their role in NF-kappaB nuclear transcription regulatory factor, as a site specific cellular adhesion blocker [47]

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Summary

Introduction

One of the growing fields of interest pertaining to nucleic acid-based gene silencing/modification is the application of antisense oligonucleotides (ASOs). The phosphodiester (PO) backbone of DNA and RNA is susceptible to nuclease mediated degradation which limits application of unmodified oligonucleotides as therapeutics. Chemical modifications of the backbone enhance the metabolic stability of oligonucleotides which enables their use for therapeutic applications. The phosphorothioate (PS) modification replaces a non-bridging oxygen atoms in the PO linkage with a sulfur atom This increases ASO stability in biological fluids and enhances their protein binding and cell uptake properties [4]. This mechanism may only work if the ASO successfully navigates past the cell plasma/endosomal membranes to target the specific mRNA of interest. The focus of this review is to highlight the development of ASOs in clinical drug development for a variety of diseases, as well as examine recent research to answer fundamental questions of cellular ASO internalization and systemic clearance

Backbone Modifications for single stranded ASOs
Diseases Targeted by ASOs
Spinal Muscular Atrophy
Factor XI for Thrombosis
Cellular uptake of Phosphorothioate Modified ASOs
Scavenger Receptor A
Conclusion
Conflicting interests
Findings
Author Contributions

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