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The emerging role of oligonucleotide therapeutics in drug discovery and development

December 6, 2021

Oligonucleotide-based therapeutics (ONs) are a relatively new class of drugs that represent one of the most prominent fields of drug discovery and development. They have the potential to treat or manage a wide range of diseases, while they can be applied in numerous therapeutic and biotechnology applications.

Nucleic acids were originally described in the 1980s as potential therapeutic agents and since then, numerous research and clinical trials were dedicated to their successful development. Currently, only a short list of nucleic acid drugs has been approved by the FDA [1]. However, it is a rapidly growing market with more than 100 nucleic acid therapeutics in the clinical pipeline, while many more are in pre-clinical development.

What are oligonucleotide drugs and how do they work?

To have a clear picture of how oligonucleotide therapies work, we first need to understand how DNA specifies and impacts the production of proteins in our bodies.

DNA is a complex, double-stranded, helical molecule that carries genetic information necessary to develop and maintain an organism. Each molecule consists of a large number of linked nucleotides, composed of a sugar, a phosphate group, and a nitrogenous base.

Certain sequences of nucleotides in the DNA are transcribed into messenger RNA (mRNA). The cell uses mRNA as an intermediate that transfers information into protein synthesis by translation.

The manipulation of DNA and RNA and the ultimate blocking of the translation can halt the production of abnormal protein related to a disorder and this is the key element that opens the way to a new concept of treating diseases.

Oligonucleotide therapeutics are composed of short chain DNA or RNA molecules, oligomers, typically generated using automated synthesizers. The fundamental basis of these agents is that they can enable intervention at a genetic level and regulate target gene expression or impede protein function, by binding to a specific sequence of a target gene or protein [2].

Their high specificity and a capability of modulating cellular pathways and targeting specific molecules leads to the development of innovative drugs against cancers and genetic diseases.

Oligonucleotides (ONs) encompass many types of therapeutics including antisense oligonucleotides (ASOs), small interfering RNA (siRNA), microRNAs (miRNAs), anti-miRNA (antagomirs), miRNA mimics (agomirs), aptamers, decoys unmethylated CpG-containing ONs. Among them, ASOs and siRNAs have been developed further and are the two most widely used strategies for modulating gene expression.

Oligonucleotide therapeutics and COVID-19

We could say that oligonucleotide therapies, although they are relatively new in the field of medicine, managed to serve as a helping hand in the fight against COVID-19. Their rational design and accelerated drug development processes made them a fast solution provider to this global health crisis.

The role of ONs was critical in diagnostics, vaccines, as well as in a variety of under development treatments. The two mRNA-based vaccines that received emergency use authorization from the FDA introduced a new era in vaccination development and had a ground-breaking impact in managing COVID-19.

What’s next?

Oligonucleotide therapeutics seem to have a bright future! Their investment and portfolio continue to grow while they promise to drug the undruggable. Genetic and untreatable diseases can now be tackled from different aspects, as new opportunities for therapeutic interventions arise. Moreover, ONs can surely fill the gap in managing and efficiently responding in future pandemics.



  1. https://www.nature.com/articles/s41565-021-00898-0/tables/1
  2. Takakura K., Kawamura A., Torisu Y., Koido S., Yahagi N., Saruta M. (2019). The Clinical Potential of Oligonucleotide Therapeutics against Pancreatic Cancer. Int J Mol Sci. 20(13):3331. DOI: 10.3390/ijms20133331