Charalampos Tzoulis: Fighting for a Breakthrough in Parkinson’s Disease

His colleagues describe him as extremely hardworking, with a restless energy in his approach to work. A determination not to let the field stand still. In recent years, one important line of Tzoulis’ research has focused on what may represent a mitochondrial subtype of Parkinson’s disease.

Mitochondria are the cell’s powerhouses, responsible for producing the biological energy the body needs to function. In a substantial subgroup of all individuals with Parkinson’s disease (approximately 20-25%), Tzoulis’ team have observed signs of marked and nearly brain-wide dysfunction in the mitochondria’s energy generation machinery, specifically the respiratory complex I.

“It appears that about one-fifth to one-quarter of people with Parkinson’s disease have such widespread mitochondrial dysfunction in their brain,” says Tzoulis.

“Mitochondria are like nuclear power plants. When they fail, you lose essential energy production, but you also get harmful byproducts that can cause extensive biological damage – so called free radicals.”

This is where the story begins to move beyond an individual research finding and toward a broader shift in how Parkinson’s disease may be understood. If a substantial proportion of patients have a definable biological subtype, that could pave the way for patient stratification and, ultimately, more tailored therapies.

But before that can happen, researchers must first be able to identify those patients using clinically applicable tests. Brain tissue is not something one can sample in routine practice, so the task is to develop accessible biomarkers that can detect the mitochondrial subtype in living patients. Developing such tools is now an important focus of Tzoulis’ research group.

Tzoulis is cautious. This is a difficult undertaking - still, the direction is taking shape: biomarkers, patient stratification, and targeted clinical trials. This is where the conversation starts to resemble treatment and research in oncology.

– With cancer, you can often take an image and see the tumor. With Parkinson’s, we don’t have that kind of direct target.

Why don’t you use biomarkers?

Tzoulis answers without reservation.

– We don’t have them. We don’t have good markers for diagnosis, stratification, or for following disease progression.

A system in transition

Tzoulis points out that the challenge lies not only in the disease itself, but also in the way clinical research is organized. To address this, he and his collaborators are developing two trial platforms: SLEIPNIR and HYDRA. Together, they represent a new approach to clinical testing, one in which several candidate treatments can be evaluated within a common framework, often with shared infrastructure and, where appropriate, a common control group. The aim is not only to move faster, but also to reduce the risk of costly late-stage failures.

Currently, a conventional late phase (Phase 2b/3) clinical trial in Parkinson’s disease can take five to eight years, require several hundred participants, and cost very large sums, with no guarantee of success. The problem is not only that breakthroughs remain elusive, but that each unsuccessful attempt consumes so much time and effort.

SLEIPNIR was designed to answer a more fundamental question earlier in development: does a candidate drug actually reach the brain and engage the biological process it is intended to affect? Treatments that fail at that stage can be filtered out before moving forward. The most promising candidates can then be taken into HYDRA, a larger and more adaptive trial structure designed to test several therapies more efficiently.

Taken together, the two platforms are intended to create a more rational pipeline for therapeutic development, one in which selection, speed, and scalability are built into the design. The goal is not simply to find a single successful treatment, but to improve the odds that genuinely effective therapies can emerge.

Hope without overpromising

For Tzoulis, however, treatment is only part of the picture. Another important frontier is prevention. What if neurodegenerative disease could be identified earlier, or even interrupted before the clinical phase is fully established?

This is one of the ambitions behind two newly awarded research centers that will work closely together: the Mohn Research Center for Neuroprotection and ICoN: Innovation Center for Neuroresilience. Both are built around a long-term shift in focus, from treating established neurodegenerative disease toward earlier detection, biological understanding, and prevention.

Treating symptoms is a major and necessary step forward, but stopping the disease before it even starts is the ultimate goal.

Back in the large conference hall, the mood remains subdued. The patients have not been presented with any breakthrough. No miracle cure.

Then comes the question many in the audience are really waiting for:

What is the most realistic timeframe for a breakthrough?

Tzoulis pauses to think before answering. Then comes the optimism. Cautious. Measured. Credible.

“Once the first brick falls from the wall, I believe the rest of the wall will come down quickly,” says Tzoulis.

“I believe that for someone diagnosed today, a breakthrough will occur within that person’s lifetime. I envision a treatment that could significantly slow the disease. And hopefully, in the near future, we will move even further upstream - towards early detection and true prevention.”

It’s not a promise. But it’s not just hope either. It’s perhaps the most realistic optimism a field with 70 negative studies can offer.

“We’re not going to give up.”