“Our gene therapy could be a success”
For more than thirty years, Markus Rüegg’s group has been studying muscles and nerves. In the interview, he talks about the development of a gene therapy to treat a severe form of a muscular dystrophy in children, the challenges – from funding to patient expectations – as well as the important role of animal research.
Your team recently published a new study on LAMA2-related muscular dystrophy – a rare hereditary disease. As a basic researcher, how does it feel to have come this far and now hold a promising therapeutic approach in your hands?
It is incredibly rewarding. Ever since I was a teenager, I have been fascinated by research and wanted to understand the fundamental processes of life. Once you understand those, you can begin to see what goes wrong in disease. The LAMA2 project began as pure basic research, and now we have a reached a point where we have a potential therapy within reach. It would be a dream come true to see this therapy alleviate the disease in affected children. Now we need to take the final steps toward clinical testing.
How did it all begin?
In my early years as a group leader at the Biozentrum, we identified binding domains in the protein agrin. Agrin is a component of the extracellular matrix – the structural scaffold that surrounds and supports cells – and is essential for the formation of synapses between nerve cells and muscle fibers. While searching for binding partners of agrin, we were the first to show that it binds to laminins and we were able to pinpoint the exact binding site. In a research proposal to the Swiss Foundation for Research on Muscle Diseases, I suggested investigating the significance of this interaction. Even back then, I suspected the work might be relevant to LAMA2-related muscular dystrophy, and I proposed testing the effect of a “mini-agrin” – a shortened, optimized version of the protein – in mouse models of the disease. Fortunately, the proposal was approved.
What is special about your latest results?
We had previously demonstrated the beneficial effects of so-called linker proteins – one of which is the aforementioned “mini-agrin” – in genetically modified mice. Our latest study shows that these linker proteins can also be delivered into LAMA2 mouse models using adeno-associated viruses (AAVs) - harmless, engineered viruses that act as carriers for genetic information. This is precisely the method used in gene therapies in humans. Our results therefore pave the way for testing this gene therapy in clinical trials as soon as possible.
Can findings from animal models be translated to humans?
Yes, because both the cause and the consequences of the disease are the same in humans. Gene therapy can stabilize muscles and nerves, improve their function, and halt disease progression. When we treat the animals immediately after birth, they develop largely like their healthy counterparts. Even older animals benefit from the therapy, and treated mice show significantly extended life expectancy.
The treatment targets not only muscles but also nerves. Why is this important?
For a long time, the disease was thought to affect primarily the muscles. Our latest data show that peripheral nerves are also impaired. If only the muscles are treated, problems in the peripheral nervous system can develop later, leading to peripheral neuropathy – a neurological disorder that mainly affects the hindlegs of the mouse. Our gene therapy ensures that the linker proteins are produced not only in muscle fibers but also in peripheral nerves, allowing us to address both disease aspects simultaneously.
LAMA2-related muscular dystrophy manifests already in newborns. What is the potential of early treatment?
In mouse models, we see striking effects: a single treatment in newborn mice is enough to almost cure the disease and even older animals benefit. This gives us hope that our gene therapy could make a real difference for patients. Because the linker proteins are already based on human gene sequences, we are close to clinical application.
If the scientific basis is so solid, what is still needed to move to clinical trials?
The production of AAVs – the actual “drug” – requires a specialized company capable of manufacturing them in large quantities under strict, controlled conditions. This is very expensive, and securing funding is extremely challenging. We have the results from animal studies, contacts with pediatricians and patient organizations, and a network of affected families. In principle, we are ready to go. However, producing AAVs and conducting clinical trials is enormously costly: the amount of AAV needed to treat a single patient costs several hundred thousand Swiss francs. We estimate that around ten million francs are needed to launch clinical trials.
Why is it so hard to get investors or pharmaceutical companies on board?
Mainly because the disease is so rare. In Switzerland, only nineteen families are affected and the numbers are also relatively small globally – about eight in one million children are affected. The situation is further complicated by the fact that, in the best case, a single treatment is sufficient to provide long-term relief from the disease, and that gene therapies are still considered high-risk.
A one-off treatment – that sounds ideal.
It is, but from a business perspective, it’s less attractive. A drug sold only once generates far less revenue than a long-term treatment. Scientifically, we have made great progress, but the market follows its own rules, something we have learned over the past few years.
To drive development forward, you founded the spin-off SEAL Therapeutics. What is the role of this start-up?
As a company, we hold the patents, which is essential for developing a therapy and bringing it into clinical testing. It also makes it easier to find industry partners who can support us with the next steps, such as large-scale AAV production; something we cannot manage on our own as SEAL Therapeutics.
Such a promising therapy raises hopes. How do you deal with that?
We are in close contact with many patients and their families, some of whom we have known for several years. Shortly after diagnosis, families often search online for information and possible therapies, and many of them find us. I regularly receive emails from parents asking whether they can already register for a clinical study. They place great hopes in our work.
How do you personally handle these expectations?
It is both motivating and a huge responsibility. Despite the hurdles, we have to keep going - because, honestly, I believe our gene therapy can succeed. Our approach is currently one of the most promising in the field. Behind the clinical facts, there are personal stories. For years now, I have received an email every Christmas from the grandfather of an affected child in Germany. Each time, he asks how far we have come and writes that he refuses to give up hope as he is convinced that “the Swiss” will make it happen. Some families are also extraordinarily committed: they manage a difficult daily life, organize fundraising campaigns, establish patient organizations, and build networks with one another. We cannot yet offer a therapy, but every day we see how urgently it is needed.
A significant part of your findings comes from animal models. Why are animal experiments indispensable for your research?
Without animal models, our research would simply not be possible. The complex pathology of LAMA2-related muscular dystrophy cannot currently be reproduced in cell cultures or organoids. Only in animal models can we determine whether our treatment works and how safe it is. This is essential, particularly for novel therapies, before they can even be considered for use in humans.
You are also personally involved in animal research. How do you deal with ethical issues?
This is a topic close to my heart. As a former chair of the animal experimentation commission of the cantons of Basel-Stadt, Basel-Landschaft, and Aargau, I have dealt with it in detail. For me, it is essential that animal experiments are conducted only when truly necessary, and that they meet the highest ethical and scientific standards. At the same time, we must not forget that many medical advances, including our own work, would not be possible without animal models. It is therefore always a matter of carefully balancing scientific benefit, medical necessity, and animal welfare.
How would you assess Switzerland’s overall approach to animal experimentation?
Switzerland handles the issue very responsibly. We have strict, well-designed regulations that clearly prioritize animal welfare and I believe this is absolutely right. In biomedical research, such as our gene therapy work, animal studies are indispensable for evaluating new approaches safely. Conducting them under clearly defined ethical conditions is a real strength of Switzerland as a research location.
Where do you still see challenges in the current system?
We are increasingly observing a degree of overregulation. For researchers, this translates into a very high administrative burden. Applications for animal experiments are extremely complex, and the entire approval process currently takes between six and twelve months. This can significantly delay projects. Given that my team members typically work on a project for three to four years, such a delay can mean that a project cannot be completed within that timeframe. The goal should be to strike a balance between maintaining high standards of animal welfare and making processes more efficient, so that innovation is not unnecessarily slowed.
What is your wish for your project?
I would like to see the gap between research and clinical application closed. We have a therapy that shows excellent results in animal models. Now we need to take the next steps and test its effectiveness in patients. It would be deeply frustrating if this approach could not be pursued simply for lack of funding. But despite all the obstacles, we will keep going with determination – because our goal is clear: we want to bring this therapy to the children who need it.