Skip to content
Back to folders

ASO: a precision technology that brings new treatment perspectives

As part of the recent evolution of precision medicine approaches in drug discovery and development, antisense oligonucleotides (ASOs) have shown promise to revolutionize the treatment of genetically defined rare disorders that in most cases are severely debilitating and still lacking an adequate treatment. In addition to rare disease, more common diseases could benefit from these advances with growing clinical ambitions starting to take shape across the sector.

When there is an error in the original design blueprint for a house, that error will be repeated in all the copies handed out to all the different craftsmen working to build the house.

It is much the same for the human body.

The DNA (deoxyribonucleic acid) in the nucleus of the body’s cells is like a schematic containing all the organism’s genetic information, much like the blueprint for the house in our analogy. That genetic information contained in the DNA is essential to the proper functioning of the human body because it enables—among other things—the production of proteins. The slightest error in that information may lead to serious or even fatal genetic diseases.

One strategy to treat such diseases is to go into the DNA and correct the underlying errors. Whereas gene therapy aims at directly correcting errors in the DNA in a non-reversible way, an American research team1 came up in 1978 with a pioneering solution to mitigate the potential risk of gene therapy. To modify not the original errors of the DNA within the nucleus, but rather to make the corrections in DNA temporary copies, called RNA (ribonucleic acid). How? By using a “synthetic” assembly of nucleic acids capable of selectively binding itself to the erroneous RNA which leads to its degradation and thus prevent —among other things—the production of defective proteins.

This discovery has paved the way for a whole new therapeutic concept: treating genetic diseases by making modifications to the temporary copies of the DNA (RNA), rather than altering the DNA itself. Those modifications are made using nucleic-acid chains called antisense oligonucleotides (ASOs), which bind themselves specifically to that RNA and block its functions such as the production of proteins.

Sixteen ASOs authorized between 1998 and 2023

Over the decades that followed, various limitations, such as insufficient biological activity, undesirable toxic effects, etc. which prevented the application of that discovery in clinical medicine were overcome one after the other.2 Technological advances have been instrumental to efficiently translate ASOs into clinical success. To date, 16 ASOs have been approved for clinical use by the US Food and Drug Administration and/or the European Medicines Agency for treatment of rare and common diseases affecting the retina, blood, muscles, nerves, and heart3.

Currently, there are several ASOs in late-stage clinical development. Those new ASOs target common diseases, such as some cardiovascular pathologies (myocardial infarction or stroke)4. They have great potential, whether for the development of new therapies or the improvement of existing ones by offering, for example, a more convenient administration frequency for patients.

Photo of researchers working on ASOs

Servier: several candidate molecules

Historically involved in neuroscience, Servier focuses its research on neurodegenerative and neurodevelopmental diseases. In 2019, the Group invested in ASOs to combat certain rare and, particularly, genetically defined forms of such diseases.

Leveraging their in-house expertise, Servier conducts all development internally, yet fosters innovation through partnerships with biotechs like Luxna and many international universities.

The development of ASOs is quite fast compared to conventional molecules, in particular in the drug discovery phase, and this is mainly linked to the ASO technology that is highly adaptable to any other type of diseases in which genetic errors has been already identified. Each new project benefits from the experience acquired and technologies developed on earlier ones.

[1] Zamecnik PC, Stephenson ML. Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci U S A. 1978;75(1):280-284. doi:10.1073/pnas.75.1.280
[2] Rinaldi C, Wood MJA. Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat Rev Neurol. 2018 Jan;14(1):9-21. doi: 10.1038/nrneurol.2017.148
[3] Collotta D, Bertocchi I, Chiapello E, Collino M. Antisense oligonucleotides: a novel Frontier in pharmacological strategy. Front Pharmacol. 2023 Nov 17;14:1304342. doi: 10.3389/fphar.2023.1304342
[4] Crooke ST, Baker BF, Crooke RM, Liang XH. Antisense technology: an overview and prospectus. Nat Rev Drug Discov. 2021 Jun;20(6):427-453. doi: 10.1038/s41573-021-00162-z
[5] Suppression of Mutant C9ORF72 Expression by a Potent Mixed Backbone Anti-sense Oligonucleotide. Tran H*, Moazami MP*, Yang H, McKenna-Yasek D, Douthwright CL, Pinto C, Metterville J, Shin M, Sanil N, Dooley C, Puri A, Weiss A, Wightman N, Gray-Edwards H, Marosfoi M, King RM, Kenderdine T, Fabris D, Bowser R, Watts JK, Brown RH Jr. Nat Med. 2021 Dec 23. Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide | Nature Medicine