1 Million Euros for Research into Early-Onset Dementia. Prof. Dr. Patrik Verstreken Receives Generet Prize for Rare Diseases

What we are developing is as close as it gets to curing a form of early-onset dementia: we are targeting the genetic cause of the disease." Prof. Dr. Patrik Verstreken (VIB – KU Leuven) is researching how a specific form of early-onset dementia can be treated with so-called ASOs (antisense oligonucleotides). This year, he receives the Generet Prize for Rare Diseases from the Generet Fund, managed by the King Baudouin Foundation. This prize comes with a research budget of 1 million euros.

Difficulty processing information and memory, mood swings, behavioural changes... the symptoms of dementia are all too familiar to many. For some, they come very early: several hundred thousand people worldwide carry a genetic mutation that inevitably causes them to develop dementia in their forties or early fifties. In Belgium, 300 to 400 people suffer from this disease. The disease strikes early and progresses rapidly.

"It concerns familial versions of Alzheimer's," says laureate Prof. Dr. Patrik Verstreken (VIB – KU Leuven). "Members of such families have a mutation on the presenilin gene. This causes the production of the protein presenilin to go wrong, leading to protein plaques in the brain, as we also see in other forms of Alzheimer's."

Prof. Verstreken's team is particularly looking at a large Mexican family with the same mutation. In other families, it is a different mutation, but always on the presenilin gene, and always with the certainty that early-onset dementia will occur.

Intervening with ASOs 

"We are investigating how we can treat them with antisense oligonucleotides. ASOs are a type of medication that ensures certain parts of the DNA are expressed differently – 'differently' usually means 'less'," explains Prof. Verstreken.

He clarifies it with the image of recipe books: our DNA is a kind of text with 25,000 recipes for the production of proteins. Each cell extracts a number of instructions from that recipe book to perform its functions. If an error (mutation) creeps into the recipe, there is also an error in the protein. This anomaly is often without much harm, but sometimes the protein starts doing something wrong. "Every person receives DNA from both parents. In short, the ASOs tell the brain cells not to follow the instruction of the mutated gene (from one of the parents), but to follow the instruction of the presenilin gene from the other parent where there is no error."

Prof. Verstreken emphasises that the work of his 25-member international team is based on and in close collaboration with other researchers. "Prof. Bart De Strooper (KU Leuven) has been working on the presenilin gene for about 30 years. And ASOs are also used in other rare forms of neurodegenerative diseases, such as Multiple System Atrophy (MSA) or Amyotrophic Lateral Sclerosis (ALS). What do we still do? ASOs are also sequences of 'letters' like DNA: we have to design them so that they exactly recognise the error in the DNA and attach to it. In collaboration with geneticist Kristel Sleegers (UAntwerpen), we can work with the genetic material of patients and analyse the sequence of the mutation to tailor the ASO to it. We hope to come up with four to eight ASOs that could help 80% of people with mutations on the presenilin gene."

ASOs cannot cross the blood-brain barrier: injecting them via the blood does not work, they must be injected directly at the base of the brain. To do this, the ASOs will be coupled with nanobodies, which have the property of being able to cross the blood-brain barrier. The procedure is not trivial, but specialised nurses have experience in this area. The method is also already approved by the drug regulatory authorities EMA (Europe) and FDA (USA), a great advantage. Patients will likely need three to four injections per year.

Further Research Thanks to the Generet Prize 

When asked when the drug will be available to patients, Prof. Verstreken understandably responds somewhat cautiously, "But I dare to hope within a foreseeable time, which in research terms means: within about ten years. A next step is to take skin cells from real patients and transform them – via the intermediate step of stem cells – into brain cells, to conduct more research on them: can we manage to switch off the function of the mutated gene? Thanks to the funds from the Generet Fund, we can create more ASOs, conduct more preclinical tests, involve more families, learn about more mutations... In short, continue working towards a solution."

About the Generet Prize 

The Generet Fund, managed by the King Baudouin Foundation, aims to make Belgium an international hub in the research of rare diseases. Since 2018, the Fund has annually awarded a prize of one million euros to a leading researcher affiliated with a Belgian research institution who conducts groundbreaking research in the field of rare diseases. The Fund does not specify which diseases it should concern: all rare diseases are eligible, as well as methodologies that can help make progress in the fight against multiple rare diseases. The Generet Prize is administered by the FNRS. 

The laureates from 2018 until now:
•    2018: Prof. Mikka Vikkula (Institut de Duve – UCLouvain), for his research into the genetic causes of vascular anomalies;
•    2019: Prof. Dr. Steven Laureys (Coma Science Group – Université and CHU de Liège) for his research into forms of altered states of consciousness due to severe brain injuries;
•    2020: Prof. Pierre Vanderhaegen (VIB-KU Leuven Center for Brain Research and ULB), for his research dedicated to brain development and where it sometimes goes wrong;
•    2021: Prof. Dr. Rosa Rademakers (VIB-UAntwerpen Center for Molecular Neurology) for her research into a rare form of dementia;
•    2022: Prof. Dr. Ludo Van Den Bosch (VIB-KU Leuven Center for Brain Research), for his research into the underlying mechanisms of a rare neurodegenerative disease;
•    2023: Prof. Dr. Sabine Costagliola (IRIBHM-ULB), for her research using human organoid technology to map two rare thyroid disorders;
•    2024: Prof. Dr. Patrik Verstreken (VIB – KU Leuven), Antisense oligonucleotides as therapy for autosomal dominant Alzheimer's disease (ASOADAD).

Additional Information: 

Discover the video of Patrik Verstreken, laureate of the Generet Prize for Rare Diseases