Conference report: The power of sharing

The conference was organised by the Swiss non-profit AGO2 Association as a satellite of the first scientific Argonautes conference. 

The event successfully united patient families, increased understanding of the symptoms, shone a light on real-life challenges and encouraged new research ideas.

We hope to be back jointly with the Argonautes conference in 2024!

Read time: 7 minutes

"This is why we are doing this," says Hamburg scientist Davor Lessel as seven-year-old Finn crawls onto his lap. Finn is patient number one. The first to be diagnosed with a disease-causing change on the AGO2 gene in 2016, which four years later was named Lessel-Kreienkamp syndrome (LESKRES). There are now 35-40 diagnosed cases worldwide, and 48 for the closely linked AGO1-related syndrome  (we collectively refer to these as “Argonaute syndromes”). A first conference physically brought together 10 affected families, several leading scientists and industry representatives, with a further 8 families joining virtually - that is 20% of known patients!

Nora Leonardi opens the conference with her personal story. Her daughter was just five months old when she started having epileptic seizures. At the end of 2020, four years after Finn's parents, her daughter is also diagnosed with a mutation in AGO2 in Switzerland. And very few answers exist to their many questions: a super rare syndrome about which little is known, likely leading to cognitive impairment, speech and motor disorders, and perhaps autism and behavioural problems. There is no treatment and no cure, and not much that can be done.

"It was so frustrating, sad and most of all I felt so isolated," says Nora Leonardi. Both she and her husband have a science background and they look for perspectives. In their desk research, they find that other patient groups have greatly advanced research and drug development for their children's diseases. 

AGO2 Association President Nora Leonardi opens the conference

And now Nora Leonardi is standing here, as president of the AGO2 association, opening the first conference on Argonaute syndromes with big goals: Bringing families together, creating awareness and informing about the syndrome, and finding new treatments. "The road to treatment is long and we are at the very beginning," says Nora Leonardi. The meeting brings together the experiences of affected families from all over the world, the knowledge of leading scientists in the field and the advice of one of the most successful parent initiatives.  

Against the Isolation

Dr. Schey moderates a panel with patient families on their lived experience

It starts with the families' perspectives - told by Ashley from the USA, mother of a 15-year-old son with AGO1 syndrome, Stephanie from the Netherlands, mother of a 5-year-old son with LESKRES and Antje from Hamburg, Finn's mother. The three talk to moderator and health economist Dr. Carina Schey about the moment when it became clear: Something is wrong. About the sometimes long road to diagnosis and the difference it makes. About the burden on the family, the importance of support, national peculiarities in the reimbursement of diagnosis and treatments, whether or not to have more children, dealing with puberty and perspectives on life.

The stories are very different and give an idea of how wide the range of developmental disability is for children and young people with Argonaute syndromes. There are many questions and requests to speak from the audience on site and in front of the screens. Parents from Germany, Denmark, Argentina, Switzerland and the USA join in. And even after the discussion, parents stand together, tears flow. "This always happens when I tell our story," says Antje. There is still a lot of sadness, helplessness and isolation. But Antje also says, and she is not the only one, how much strength there is in sharing these stories.

What does research know?

She didn't know any of the families that are here before, says Prof. Amélie Piton, who studies AGO1 in France. She only knew the descriptions in the scientific publications. That is why it is a particularly emotional moment for her to meet some of these children and their parents here in Regensburg. "I know they have no choice," Piton says with audible emotion in her voice. "But I admire them very much for what they are doing here."

Piton does research in Strasbourg, Dr. Davor Lessel and Prof. Hans-Jürgen Kreienkamp in Hamburg on disease-causing mutations in the AGO1 and AGO2 genes, respectively. Lessel emphasises that it makes sense to look at both genes together because they produce a similar, if not the same, syndrome.

Prof. Piton, Dr. Lessel, Prof. Kreienkamp and Prof. Meister share research updates and answer questions from families

Lessel is one of the first to describe the Lessel-Kreienkamp syndrome, which is also named after him. Like his colleagues, he is live in Regensburg and at the beginning of his talk he takes the audience on a journey through genetics and the development of rare diseases. More than 50 percent of all neurodevelopmental disorders are caused by so-called de novo mutations, which occur for the first time in the egg or sperm cell or during early cell division. "It is important to know," says Lessel with regard to parents, "that you have done absolutely nothing wrong with a de novo mutation." Every one of us carries such mutations - the only question is at what point in the genome. In a critical region, this mutation can cause a syndrome with severe symptoms. 

It is known that a mutation in over 1,000 of our 20,000 genes can lead to a neurodevelopmental disorder, adds Amélie Piton. "Each of them is rare, but all of them taken together, they are no longer rare at all."

The range that was already evident in the three families on the podium also continues in the description of the symptoms that have been scientifically recorded so far. For the first publication on Lesssel-Kreienkamp syndrome, Lessel had collected the reports of a large number of colleagues in Germany and abroad. But these reports left many gaps: How pronounced are cognitive, motor and linguistic impairments, at what age do behavioural problems become noticeable, what medications were used to treat epileptic seizures?

"We are missing important medical information and there is information we can only get from you," Lessel addresses the parents. He says they now have a colleague who will conduct as many interviews with parents as possible. "That's the only way we can understand," says Lessel. He says he has already gained new insights into recurring symptoms during the conversations that day.

But that is only part of the future research. Only when they better understand what exactly happens as a result of the mutations in the AGO1 and AGO2 genes, children could be better diagnosed and cared for, and at some point in the future also treated and cured, says Piton. Cell and animal studies will be necessary for this. Piton, Lessel and Kreienkamp are already working on this and are hoping for support from scientists researching the Argonaute genes, from pharmaceutical companies and private research companies. Incidentally, it was no coincidence that the conference took place in Regensburg. Beforehand, the world's leading experts in Argonaute research had met at the same place at the invitation of Regensburg's Professor of Biochemistry, Gunter Meister, and several stayed for the Argonaute syndromes conference.

Family and scientists who attended the first Argonautes and the first Argonaute syndrome conferences

What can be done next?

About 85 children and adolescents diagnosed in the whole world, that is incredibly few. And even though there are dedicated scientists working on AGO1 and AGO2, ultra-rare diseases are not the most grateful field of research. "If there's one person you can learn from, it's Dr. Leslie Gordon." That's what scientist Lessel had said to AGO2 co-founder Nora Leonardi. And now this same Leslie Gordon was a virtual guest at the first AGO2 conference.

Dr. Leslie Gordon is the founder of the Progeria Research Foundation (PRF), which has been instrumental in researching and treating Progeria, a very rare progressive genetic disorder that causes children to age rapidly, for 20 years. "I'm a mom first and foremost, and that's where all this comes from," Leslie Gordon says at the very beginning. Her son Sam was diagnosed with Progeria in 1998 at the age of 22 months, and in 1999 Leslie Gordon, a medical doctor herself, and her husband founded the PRF, which remains dedicated to finding a cure for the deadly disease.

At the time, almost no one was working on researching Progeria, it was not even known to be a genetic disease, there was no research funding and no place for families and doctors to go for information or treatment. The PRF built a patient registry - "perhaps the most important step, not only to connect families, but also as a basis for research," says Gordon. 218 research teams in 26 countries have now conducted research on Progeria. PRF brought scientists together in 13 conferences, published manuals for parents and professionals. In 2020, the first drug to treat Progeria was approved in the US. It adds years to the life expectancy of children and adolescents. "We have ways to treat it, but we don't have a cure yet, we're somewhere in the middle," says Leslie Gordon.  

Progeria's path to a treatment. Red = steps that could be taken only once the gene was identified. (c) Progeria Research Foundation

In a final presentation at the conference, Michael Pettigrew from the US biotechnology company BridgeBio Pharma gave valuable tips on the conditions under which pharmaceutical companies are interested in taking potential drugs forward into clinical trials. 

Finally, Leslie Gordon says that so much has happened in recent years, especially technologically. She hopes that AGO1 and AGO2 will progress much faster than Progeria, where it took years to find the genetic cause of the disease. "You're already ahead of the game there and it's so important what you're doing," Gordon says to the audience in Regensburg and in the live stream. "No one can do it as well as you!"

We hope to see you again in 2024 at a satellite meeting of the next Argonautes conference!

We'd like to thank the journalist parent who wrote this report.