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Oligos – The medicines of the future?

What if we could silence certain genes to treat a wide range of medical conditions, from genetic conditions to infectious diseases, and even cancer? It may sound like science fiction, but for some rare diseases it’s already a reality through the use of oligonucleotide therapeutics, sometimes referred to as the medicines of the future.

But what are oligonucleotides, or “oligos”, how do they work and how can this new form of drug therapy target so many different types of disease? DNA is the hereditary material in humans and all living organisms, which stores our genetic information. DNA is a long polymer made from repeating units called nucleotides and consists of two strands of polynucleotides that form a spiral called a double helix. Throughout nature, nucleic acid polymers are used for storage, transfer, synthesis, and regulation of genetic information.

Following the discovery of DNA’s structure and role in the storage and propagation of genetic information, the scientist Francis Crick proposed the concept of the central dogma of biology. This stated that DNA is transcribed into RNA, which in turn is translated into proteins.

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The sequencing of the human genome and the rapid progress of technologies enabling its manipulation have led modern-day scientists to challenge Crick’s central dogma theory, that DNA leads to RNA, which leads to proteins. In fact, current thinking indicates that genetic information can flow in both directions between DNA and RNA, and far from playing an intermediary role, RNA is a pivotal means by which the genome can be altered.

“Thus, the role of nucleic acid polymers within biology has grown from information storage and heredity for DNA to information transfer, protein synthesis, and regulatory mechanisms for RNA.”

Thus, the role of nucleic acid polymers within biology has grown from information storage and heredity for DNA to information transfer, protein synthesis, and regulatory mechanisms for RNA. In line with these advances, RNA biology is a key research focus for therapeutic intervention at AstraZeneca, and one that complements our conventional approaches such as small molecule, protein engineering and antibody-based therapeutics.

Therapeutics targeting RNA offer enormous potential. Not only can they be used to tackle the 80 percent of translated proteins that are difficult to modulate with either small molecule drugs or antibodies, but they can also be used to target the regulatory non-coding RNA. This opens up a vast number of new targets for disease intervention, and oligonucleotide therapeutics thus form potentially the most important class of next generation therapeutics.

“Oligos offer new opportunities for therapeutic intervention because they act inside the cell and can be designed to target essentially any gene in our genome.”

Oligonucleotide therapeutics are based on short single- or double stranded chemically modified RNA molecules that are 12–30 nucleotides in length. Oligos offer new opportunities for therapeutic intervention because they act inside the cell and can be designed to target essentially any gene in our genome. They are designed to seek out, bind to and destroy or re-code disease-causing RNA, which in turn either prevents or modulates the translation of that RNA into proteins within our cells.

Thus, medicines based on oligonucleotides treat diseases by decreasing the amount of disease-causing protein or by increasing the production of a protein to restore it to normal levels. Advances in RNA therapeutic chemistry to increase stability, potency and safety of these molecules is unlocking a new wave of RNA therapies.

Additionally, because RNA-directed drugs can be rationally designed based on the target RNA sequence, therapeutic oligonucleotides offer significant advantages in drug discovery efficiency. However, in order for these RNA modalities to reach their full potential, further research is required to deliver them efficiently to target organs and tissues.

Since 2020, AstraZeneca is investing in the development of a state-of-the-art oligonucleotide platform at our Gothenburg R&D site, and we’ve recruited oligonucleotide experts from around the world. This strong investment will drive forward our understanding of these therapeutics, enabling us to secure access to different types of oligonucleotides and modulate novel targets. We’re also developing oligonucleotide-based therapies for new and emerging disease targets across our therapy areas through external collaborations with biotech companies, and we have several oligonucleotides in clinical phase development.

We have also strong collaborations with academia. One such partnership is with OligoNova, a Swedish national initiative for oligonucleotide therapies organized under the Wallenberg Center for Molecular and Translational Medicine, and part of the SciLifeLab Drug Discovery and Development platform. Together with other actors from biotech, academia and politics, we collaborate to create the best possible conditions for groundbreaking therapies that can be implemented within the healthcare system and reach those we all put first – the patients.

 

Shalini Andersson, Vice President, Oligonucleotide Discovery, AstraZeneca

 

This Perspective was originally written for NLS magazine No 01 2023, out February/March 2023