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 particularly rare and genetically driven or inherited disease. 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.
Nine ASOs authorized between 1998 and 2020
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 other2. Thanks to those advances, ASO technology has delivered on its promise, and nine ASOs were approved in several countries around the world between 1998 and 20203 for treatment of rare genetic diseases affecting the retina, blood, muscles, nerves, and heart.
The benefits for patients are plain to see, and this has demonstrated the interest in ASOs. For example, children suffering from spinal muscular atrophy affecting even their respiratory function benefited from improvements in their motor functions after an injection of ASO and were even able to regain certain simple postures, such as sitting.
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).3 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.
Servier: several candidate molecules
Historically involved in neuroscience, Servier focuses its research on neurodegenerative diseases, more specifically on movement disorders. In 2019, the Group invested in ASOs to combat certain rare and, particularly, genetically defined forms of such diseases.
“Three years later, we have seven ongoing projects,” explained Johannes Krupp, Program Director for Neuroscience Research. Four of them are being conducted in-house and two in partnership: one with Mina Therapeutics and another one with MJJ Biotech and Ranger Biotechnologies. One of those projects is aimed at treating atypical parkinsonism. It will soon complete its preclinical phase, giving rise to hopes that human studies could begin in 2024 and that a possible treatment will be available to patients by 2032.”
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.
So, what is next?
Like every laboratory working on ASOs, Servier’s objective is to bring forward new therapeutic solutions to patients affected by genetically defined rare diseases4,5 and, potentially, to target more common diseases such as Parkinson’s disease.
Furthermore, there is growing consideration of the application of this technology more broadly that just neuroscience: “We have recently launched a neuro-oncology project, which may one day give rise to innovative solutions to treat glioblastoma, a brain cancer,” explained Ross Jeggo, Director of the Neuroscience and Immuno-inflammation Therapeutic Area.
“We have recently launched a neuro-oncology project, which may one day give rise to innovative solutions to treat glioblastoma, a brain cancer,” explained Ross Jeggo, Director of the Neuroscience and Immuno-inflammation Therapeutic Area.
Servier made the choice to develop new in-house expertise in the field of ASOs, starting work on first ASOs in 2019. In 2022, these activities will be consolidated into an ASO Program, devoted to capitalizing on the experience the Group has acquired so far, and refining and focusing its continued future efforts across our multiple ASO projects to accelerate the delivery of therapeutic candidates for first administration to humans. Servier is developing significant and differentiating scientific and medical expertise to apply this ASO technology to rare and ultra-rare diseases and continue our ambition to develop precision medicine approaches for the benefit of patients.
 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
 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
 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
 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