Leiden, Holland, 20 November, 2023, at 9:59 AM.

A small group of people is gathered in a corner room adorned with large glass windows. The weather outside is typical autumn - grey and wet. A large clock is centrally placed in the room, steadily counting down to 10:00, as if a rocket was about to be launched into space. Today, it is not a rocket, but a small pill bottle that is the focus of everyone's attention.

"I know it sounds completely crazy, but suddenly the sun started shining just when the clock struck 10:00, and you couldn't help but smile - it was absolutely fantastic."

Anders Nykjær is a trained medical doctor and works as a professor in biomedicine. On November 20 this year, a significant milestone was reached in his research career when the research he had been working on for over 30 years materialized into a small white pill and was given to a human being for the first time.

"I thought, it can't be true. What every researcher hopes for is that at some point, you get to apply what you have found, which seemed so abstract and uninteresting to anyone, at least in the first few years. And now, you stand there and see a person take a pill based on the research you have been working on for many years with colleagues."

Suddenly, we discovered an important receptor
To understand how it all ended up here, one must rewind time to the mid-1990s.

A group of proteins caught the interest of Anders and his research colleagues. It was a time when the human genome was still unknown, and various biochemical methods were employed to discover something new.

"And that's exactly what we did," says Anders.

What the research group found was a small protein receptor called "sortilin," belonging to a family known as VPS10 domain receptors.

"And people were already falling asleep when hearing about this. No one cared to hear about this at that time, and no one knew our names in the neuroscientific environment."

Fortunately, the Lundbeck Foundation showed interest in the project and granted 50 million Danish kroner in the mid-2000s.

"The foundation told us: 'Now you just need to pursue the function of these proteins, and you can do it freely – just learn something’. And it's extremely rare for research to be made so free.'"

The investment proved fruitful after more than 10 years. During these years, the research group, in collaboration with colleagues at Yale University, discovered that the sortilin receptor binds to a protein called progranulin, thereby contributing to the presence of this protein both inside and outside the cell.

"And what was known at that time was that insufficient progranulin was closely linked to the development of a specific type of dementia called frontotemporal dementia."

Frontotemporal dementia is one of the most aggressive forms of dementia, where the neurons and functions of the brain break down relatively quickly. The lifespan is often no longer than 5 years after the diagnosis of the disease, and it is often directly hereditary.

"So I suggested, together with a researcher from Yale University, what if we block sortilin so it can't bind to progranulin? That way, we could give patients more of what they lacked, thus normalizing the condition."

From Petri Dish to Pill
After several unsuccessful attempts by the established pharmaceutical industry, Anders and his colleague Mads Kjølby, in collaboration with Lundbeck BioCapital, set out to develop a chemical compound that could both penetrate the blood-brain barrier, target the specific receptor precisely, and be formulated into a pill that could be swallowed.

"We've been through a lot of preclinical studies in various animal models, and we've had chemists investigating how to make a stable substance, how to encapsulate it in the right capsules, can be absorbed, and in large enough quantities. There are a whole lot of things that need to come together. And now we've reached that point and obtained permission to conduct the first trial."

The goal of the experiment is initially to investigate the tolerated dosage, after which patients diagnosed with frontotemporal dementia will be treated, and the clinical effect of the tablet treatment will be assessed.

It has been 30 years since the first discovery of the protein, and the first steps toward a real treatment are now being taken. For Anders Nykjær, it is a dream come true and a very clear proof of what basic research can achieve:

"It means that the time and effort we have invested now makes sense. Our findings originated from free research, where we followed our curiosity and intuition because there could be something exciting here. A bit like when Columbus sailed towards the unknown West."

Potential for Both Treatment and Prevention
According to Anders, sortilin is a crucial factor in many neurodegenerative diseases, and with in-depth knowledge of the mechanisms involved, it opens up the possibility of not only treating the sick but perhaps also the healthy before they are affected by the disease. However, Anders emphasizes that for now, the focus is on finding a treatment for patients:

"People often talk about treatment to prolong patients' lives, but that's not always the goal. The aim is to prolong their quality of life so that they feel good as long as they live. They may be starting to develop dementia, but I know they would have been much worse off without treatment."

The first pill has now been taken, and many steps are still ahead before the medicine can reach the market. Anders does not doubt that they are on the right track with this treatment, and he is also clear about what he looks forward to the most:

"I would like to meet a patient who has received our treatment, greet him or her, and hopefully see a smile or something else. If that were to happen before my planned retirement age, I think I would retire a little earlier in the joy of having achieved something good, and now there's nothing left but to be happy about it. And the patient should be happy – that's the most important thing."

• Read the press release

More information, contact
Professor Anders Nykjær
an@biomed.au.dk
+45 28992384