On March 10th, at the European Parliament, Mara Dierssen and Raphael de la Torre took stock on the advances of the project Tesdad. Ever since it was initiated, the Jérôme Lejeune Foundation has been invested in this scientific initiative, funding a large part of the work. Review of the story of this project and its first results.
First of all, medical research is about people who are passionate about a subject and devoted to their patients. It is the case for Professor Mara Dierssen. Head of the neurobehavioral analysis group within the programme “gene and pathologies” from the Centre for Genomic Regulation (CRG) of Barcelona, Mara is a scientist who is deeply dedicated to people with Down Syndrome.
This lively and determined woman truly has at heart to develop a treatment and, more widely, to advance the cause of people living with genetic intelligence diseases. As proof, the CD she published a while back with her band, of which the songs were written by people living with Down Syndrome.
- A bet based upon a feeling
In 2010, both the Sisley and the Jérôme Lejeune Foundation rewarded her work, which falls in line with Professor Jean Delabar’s pioneer work. The goal of this research is to find one or several molecules enabling the intellectual capacities of Down Syndrome patients to be improved. Among the genes which overexpress in these patients, several are suspected to be partly responsible for their intellectual disabilities. One of them, the gene DYRK1A, codes for an enzyme involved in controlling the functioning of neuronal cells and cerebral development. The researchers thus came out with the hypothesis according to which the limitation of the production of the enzyme DYRK1A should reduce the patients’ intellectual dysfunction. The Foundation supports this intuition and funds Professor Jean Delabar’s research. The tests carried out on the mouse models for Down Syndrome indeed confirm the role of the gene DYRK1A. In these mice, the fact of inhibiting DYRK1A improves their behaviour. The proof-of-concept is set.
Mara Dierssen plays a very important part in these studies by making a significant contribution to the definition of the physiological role and to the dose dependant effects of the chromosome 21 on neuronal development, learning, memorisation, and the neurodegenerative process.
After her first work, Mara Dierssen wanted to dig deeper. Jean Delabar had identified a natural inhibitor for DYRK1A - Epigallocathechin Gallate (EGCG) - which is extracted from green tea. The product is free from any toxicity and completely safe. She therefore initiated a therapeutic clinical trial. She thus started the conception and implementation of a first clinical trial on humans.
Five years later, she smiles when speaking of the support received from the Jérôme Lejeune Foundation for this clinical trial: “You had faith in this project and that was the most important. You placed a bet on this trial.” Indeed, though convinced that her hypothesis was right and that it was time to launch the first clinical trials on humans, Professor Mara Dierssen and her team seriously lacked the necessary means for the development and initiation of the project. The Foundation, who knew of this project, that it had followed since its initiation, decided to support the project and offer its financial help as well as a scientific and medical back up.
- An ambitious study
To conduct her project, Mara Dierssen associated with Rafael de la Torre, director of the pharmacology and human clinical neurosciences research program at the IMIM (Institut Hospital del Mar d’Investigacions Mediques) in Barcelona. Together, they conceived and implemented the clinical trial TESDAD. A group of 87 patients living with Down Syndrome and aged from 18 to 30 years old is thus put together. All the patients included in the study protocol are treated with EGEG for a year, and some of them, 27 to be precise, are submitted to complementary neuro-imagery explorations (functional magnetic resonance imaging, MRI) and neurophysiological explorations (transcranial magnetic stimulation, TMS).
The first TESDAD analyses are already very promising. They show an improvement of memory and executive functions, such as decision making. Confident in the results of TESDAD, Rafaël de la Torre and Mara Dierssen are already thinking of launching the second phase of the study, which will include two groups of children with Down Syndrome. The first group will include patients from 2 to 6 years old and the second, patients from 6 to 12 years old.
- Giving research a European dimension
Having got to the end of the first stage of the clinical trial, Mara Dierssen and Rafaël de la Torre wish to give their research a new impulse and speed things up. For this, they called upon the European institutions. The research department could select their project and provide a budget.
They therefore handed in a project called ID-THERA in 2014. This “global” multicentre project, in the continuity of the TESDAD trial, aims at further developing the existing results thanks to the implementation of better adapted tools, new trials on different groups and the development of stimulation techniques in addition to the ECGC treatment. Despite the initial promising results, the European authorities turned down the project.
The Jérôme Lejeune Foundation, anxious for this project to succeed, is thinking about providing extra support to Rafaël de la Torre and Mara Dierssen’s teams. After having met the team of researchers in Barcelona at the end of January, the Foundation and the Institute are thinking about the technical and financial conditions required to initiate a new partnership with this team of pioneers, who has been able to successfully carry out a first promising scientific experiment.
Question to Mara Dierssen
Could you have imagined you would be leading a clinical trial on Down Syndrome?
M. Dierssen: Originally, I’m a physician. I graduated from the medical school of the University of Cantabria. I thus always had in mind that the ultimate goal of my research would always be to serve human beings, but since I have been working in preclinical research, I have found out how difficult and very long it takes to obtain any clinical result that can actually be used. It is therefore an incredible gift to be able to lead a clinical trial.
- Birth of a collaboration
How did your collaboration begin?
M. Dierssen :
After Jean Delabar’s publication concerning the effect of EGCG on mouse models, we started using our own mouse models, and we were able to further develop his conclusions. I therefore decided to start a clinical trial. I then went to the second story of our building to the department of neuropharmacology. Rafaël was there, I explained the project to him and I remember very well his interest in this trial and in the important neurobiological implications it could have. This interest was crucial. I was finally given the opportunity to start the clinical trial with a safe product and great biological work as a back up to guide the whole of the work being carried out. Personally, it was an incredible experience. Not only because this collaboration was scientifically fascinating and exciting, but also because I learned so much in neurobiology, clinical practice, and interpretation!
R. de la Torre : When Mara came up to me six year ago to talk about this project on green tea, I wanted to take a new turn in my career. At the time, I was at the verge of completing two studies, one in clinical pharmacology, the other in cognition; 20 years devoted to cognition and 15 years to clinical research on nutrition. In fact, Mara was in the right place, at the right time. Her project was a perfect link between nutrition and cognition; it was ideal. Back then, I only had a very superficial knowledge of genetic intelligence diseases. Mara’s contagious enthusiasm helped me fill the existing gaps.