At the heart of the award-winning research project “Antisense oligonucleotides inducing genetic compensation as therapeutics for rare diseases (ASO-2-Rescue)” is the gene utrophin, which is structurally similar to the dystrophin gene and can partially fulfill its function. To activate utrophin, the researchers are targeting an unexpected spot: not utrophin itself, but the defective dystrophin gene. Using tailor-made molecular tools called antisense oligonucleotides, they intervene in the reading of the dystrophin gene. As a result, the cell’s blueprint for dystrophin is degraded. This degradation signals the cell to increase utrophin production. What started as two initial approaches at the dystrophin gene has grown to nine. About 90 different molecules have been designed and tested in both human and mouse muscle cells. Several promising candidates trigger the desired effect, so far demonstrated at the RNA level—the gene’s transcript.
The most promising molecules are now also being tested beyond cell culture: the team has established a procedure to trial them directly in the muscle of mice. Initial test series have already been completed, and further results are expected soon. In parallel, the team is developing a new model that exhibits pronounced disease symptoms and supplements the models established so far; it is intended to be made available to the scientific community in the future.
On the way to application: From laboratory experiment to muscle testing
It is currently being examined whether the observed effect can also be confirmed at the protein level, and if more functional utrophin is actually produced in the muscle cells. Initial samples are already under analysis. The team has also taken the first steps toward applying the same principle to two other rare diseases: Marfan syndrome (gene FBN1) and laminopathies (gene LMNA). In parallel, they are seeking further funding to move the most promising candidates toward clinical development.
“We are very grateful to the Eva Luise and Horst Köhler Foundation for enabling this important progress,” says the team led by Didier Stainier. We as a foundation can only return this thanks: Sincere thanks for this dedicated research, which creates hope and opens up new perspectives!
Professor Dr. Didier Stainier in Interview
Professor Stainier, in 2025 you and your team were awarded the Eva Luise Köhler Research Award. What has this award and the associated funding concretely enabled for your work?
A great deal. Thanks to the funding, we were able to expand our testing program significantly beyond our original plans. Instead of around 50 molecules as initially intended, we designed and tested about 90. This was crucial in identifying the most promising candidates in the first place. Additionally, we were able to present our results at the annual meeting of the Muscular Dystrophy Association in Orlando. Exchange with other research groups there proved to be invaluable for advancing the project.
What is the aim of your project, and where are you on the path towards it?
Our goal is to specifically activate the body’s own compensation mechanism so that it compensates for the loss of a gene whose mutation causes the disease. In the case of Duchenne muscular dystrophy, this operates via the related utrophin gene. Over the past year, we showed that this mechanism can be reliably and reproducibly triggered in muscle cells using our molecules. We are now working to confirm this at the protein level and to further develop the best candidates toward clinical application. It’s a long road, but we are making tangible progress.
How can this research concretely help people with Duchenne muscular dystrophy or other rare diseases?
Duchenne is still incurable today, and the disease progresses over the years. If we succeed in compensating for part of the lost muscle function via utrophin, this could slow down disease progression and give affected individuals more quality of life and independence over a longer period. That is what we are working hard to achieve.
What are the next steps?
We want to confirm that our approach also produces the desired effect at the protein level. We also want to complete testing in the mouse model. The most promising candidates should be developed to a stage where they are patent-protected and ready for clinical development. In parallel, we are continuing our initial work on two further genes, FBN1 and LMNA.
Prof. Dr. Didier Y. R. Stainier is Director at the Max Planck Institute for Heart and Lung Research in Bad Nauheim and is among the world’s leading scientists in the field of developmental genetics. He studied biology at Brandeis University (USA) and earned his doctorate at Harvard University. After a research stay at Harvard Medical School, he led his own laboratory for many years at the University of California, San Francisco, before joining the Max Planck Institute in Germany in 2012. His scientific interest centers on the genetic and molecular mechanisms of organ development and regeneration. Through his research into so-called transcriptional adaptation, he discovered a fundamental biological principle that opens up potential new therapeutic approaches for genetically based diseases. He has received numerous awards for his research, including several prestigious ERC Advanced Grants. Professor Stainier was the first recipient of the Christiane Nüsslein-Volhard Prize from the European Zebrafish Society. For the “ASO-2-Rescue” project, he was awarded the Eva Luise Köhler Research Prize in 2025 together with his team members Dr. Christopher Dooley and Lara Falcucci.
