WPC 2026 Update: The Current State of the Science - the Race Toward Disease-Modifying Therapies

From alpha-synuclein antibodies to genetic therapies and platform trials, researchers are pursuing multiple paths toward slowing—or someday stopping—Parkinson's disease progression.

For decades, Parkinson's disease treatment has focused primarily on managing symptoms.

And to be clear, those treatments have changed countless lives.

Medications like levodopa, dopamine agonists, deep brain stimulation, physical therapy, exercise, speech therapy, and occupational therapy can dramatically improve function and quality of life.

But there has always been one frustrating reality:

None of these treatments have definitively been shown to slow the underlying disease process.

They help people live better with Parkinson's disease.

They do not yet stop Parkinson's disease from progressing.

That is why one of the most exciting themes at the World Parkinson Congress was the growing focus on disease-modifying therapies, often referred to as DMTs.

Rather than simply treating symptoms, disease-modifying therapies aim to slow, alter, or interrupt the biological processes driving Parkinson's disease itself.

In other words, the goal is not simply to help someone move better today.

The goal is to help preserve brain function tomorrow.

Why Has Developing Disease-Modifying Therapies Been So Difficult?

One of the biggest challenges in Parkinson's disease research is timing.

As discussed in previous articles, researchers increasingly believe Parkinson's disease may begin 10–20 years before diagnosis.

By the time tremor, stiffness, slowness, or balance problems become obvious, substantial neuronal loss has often already occurred.

Researchers frequently estimate that 50% or more of dopamine-producing neurons may already be gone by the time symptoms emerge.

This means many therapies may be starting after significant damage has already occurred.

Another challenge is that Parkinson's disease is biologically complex.

There is no single pathway to target.

Instead, researchers are trying to address multiple interacting processes including:

• Alpha-synuclein aggregation

• Lysosomal dysfunction

• Mitochondrial dysfunction

• Neuroinflammation

• Genetic risk pathways

• Cellular energy failure

• Impaired protein clearance

The result is a rapidly expanding treatment pipeline that looks very different from what existed even ten years ago.

Target #1: Alpha-Synuclein

If there was one target discussed more than any other at WPC, it was alpha-synuclein.

As we discussed in the previous article, alpha-synuclein is a normal protein that becomes problematic when it misfolds, aggregates, and forms Lewy bodies.

Researchers are pursuing several strategies:

• Preventing alpha-synuclein aggregation

• Breaking apart existing aggregates

• Improving protein clearance

• Blocking cell-to-cell spread

• Reducing alpha-synuclein production

Prasinezumab

One of the most closely watched therapies is Prasinezumab.

Prasinezumab is a monoclonal antibody designed to bind alpha-synuclein and potentially reduce its spread throughout the nervous system.

Early studies, including the PASADENA trial, did not meet their primary endpoints.

At first glance, this sounds disappointing.

However, longer-term follow-up suggested participants who continued treatment may have experienced slower progression over time.

While far from a definitive success, these findings have kept interest alive and additional studies continue.

One of the strongest messages from researchers was that failed trials do not necessarily mean failed science.

Sometimes they simply mean we have not yet identified the right patients, the right timing, or the right outcome measures.

Target #2: GBA1 & Lysosomal Dysfunction

One of the most promising areas of Parkinson's research focuses on the cell's waste-disposal system.

The GBA1 gene produces an enzyme called glucocerebrosidase (GCase), which helps cells clear damaged proteins and waste products.

When this system becomes impaired, alpha-synuclein may accumulate more easily.

Ambroxol

One of the most exciting therapies currently being studied is Ambroxol.

Originally developed as a cough medication, Ambroxol appears capable of increasing GCase activity and improving lysosomal function.

Researchers hope this will improve protein clearance and reduce alpha-synuclein accumulation.

The ongoing ASPRO-PD Phase 3 trial is evaluating whether these biological effects translate into meaningful clinical benefits.

ACTIVATE Trial

The ACTIVATE study is evaluating Pariceract, a therapy designed to enhance GCase activity.

Unlike many previous studies, ACTIVATE specifically enrolls individuals with GBA1 mutations, representing a move toward precision medicine and targeted treatment approaches.

Target #3: LRRK2

LRRK2 is one of the most important Parkinson's disease genes identified to date.

Researchers believe abnormal LRRK2 activity may contribute to:

• Inflammation

• Lysosomal dysfunction

• Cellular stress

• Neuronal injury

The goal of LRRK2 therapies is to reduce excessive activity of the LRRK2 protein.

LUMA Trial

The LUMA trial evaluated a LRRK2 inhibitor in Parkinson's disease.

Although the Phase 2 study did not meet its primary clinical endpoint, researchers successfully demonstrated that the drug reduced LRRK2 activity biologically.

This distinction is important.

Sometimes researchers can confirm they hit the biological target even if they do not yet see the clinical outcomes they hoped for.

Denali & Lighthouse Programs

Additional LRRK2-targeted programs remain ongoing.

These studies continue exploring whether modifying LRRK2 activity can alter disease progression, particularly in individuals carrying LRRK2 mutations.

Target #4: Mitochondrial Dysfunction

Another major theme at WPC was mitochondrial dysfunction.

Mitochondria are the energy generators of cells.

Dopamine-producing neurons require enormous amounts of energy and appear particularly vulnerable when mitochondrial function becomes impaired.

Many researchers now view mitochondrial dysfunction as one of the central drivers of Parkinson's disease progression.

NOPARK Trial

One of the most anticipated mitochondrial studies is the NOPARK trial.

NOPARK is evaluating a nicotinamide-based therapy designed to improve mitochondrial function and cellular energy production.

Researchers hope that supporting mitochondrial health may improve neuronal survival and slow disease progression.

Results are still pending.

Target #5: Neuroinflammation

One of the biggest shifts in Parkinson's disease research over the past decade has been growing recognition of the role of inflammation.

Researchers increasingly believe that immune activation and neuroinflammation may contribute to ongoing neuronal injury.

The challenge is that inflammation is complicated.

Some immune responses may be protective while others may be harmful.

This makes designing anti-inflammatory therapies particularly difficult.

DAPA-PD

The DAPA-PD trial is exploring whether targeting inflammatory pathways can alter disease progression.

Researchers hope to better understand whether reducing harmful inflammation may help preserve neuronal function over time.

This remains one of the most rapidly evolving areas of Parkinson's research.

Why Exercise Keeps Appearing in These Conversations

One of the most fascinating observations from the conference was how often exercise appeared alongside discussions of disease-modifying therapies.

The reason is simple.

Exercise influences nearly every biologic pathway researchers are trying to target pharmacologically.

Exercise has been shown to influence:

• Alpha-synuclein biology

• Neuroinflammation

• Mitochondrial function

• Neurotrophic factors

• Synaptic plasticity

• Cerebral blood flow

• Gut microbiome health

Unlike most medications, exercise exerts what researchers call a pleiotropic effect, meaning it affects many biological systems simultaneously.

Several speakers described exercise as the only intervention currently showing consistent evidence of influencing multiple disease pathways at once.

A New Way of Running Clinical Trials

Another exciting topic discussed at WPC was the evolution of clinical trial design itself.

Traditional Parkinson's trials are:

• Expensive

• Slow

• Resource-intensive

• Often limited to testing one therapy at a time

Researchers are now adopting innovative approaches designed to accelerate discovery.

Platform Trials

Platform trials allow multiple therapies to be tested simultaneously within the same study infrastructure.

Think of them as clinical trial "hubs" rather than individual stand-alone studies.

This approach allows researchers to:

• Test more therapies

• Reduce costs

• Improve efficiency

• Identify promising treatments faster

ACT-PD Platform Trial

One of the most exciting examples is the Edmond J. Safra ACT-PD Platform Trial.

Rather than testing a single therapy, ACT-PD is simultaneously evaluating multiple potential disease-modifying treatments, including:

• Telmisartan: Telmisartan is a medication traditionally used to treat high blood pressure, but researchers have become interested in it for Parkinson's disease because of its potential effects on inflammation and brain health.

  Telmisartan activates a receptor called PPAR-γ (Peroxisome Proliferator-Activated Receptor Gamma), which plays an important role in regulating inflammation, metabolism, and cellular stress responses.

  Researchers believe Telmisartan may:

  • Reduce harmful neuroinflammation

  • Protect dopamine-producing neurons from injury

  • Improve mitochondrial function

  • Reduce oxidative stress

  • Support healthy blood vessel function in the brain

  Because inflammation is increasingly recognized as one of the major biological drivers of Parkinson's disease progression, Telmisartan is being investigated as a potential disease-modifying therapy rather than simply a blood pressure medication. Researchers are excited because it is already widely prescribed, relatively inexpensive, and has a well-established safety profile.

• Terazosin: Terazosin is another medication originally developed for a completely different purpose—treating enlarged prostate (BPH) and high blood pressure.

  Researchers became interested in Terazosin after discovering it activates an enzyme called phosphoglycerate kinase-1 (PGK1), which plays a key role in cellular energy production.

  This is particularly important because one of the hallmarks of Parkinson's disease is:

  • Mitochondrial dysfunction

  • Reduced cellular energy production

  • Increased vulnerability of dopamine-producing neurons

  Terazosin appears to:

  • Increase glycolysis (the process cells use to generate energy)

  • Improve ATP production

  • Support mitochondrial health

  • Increase cellular resilience under stress

  Several observational studies have suggested that people taking Terazosin may experience slower Parkinson's progression compared to those taking similar medications that do not affect cellular energy pathways. Researchers are excited about this one because it directly targets one of the most important biologic themes emerging in Parkinson's disease research: energy failure within vulnerable neurons.

• Ursodeoxycholic Acid (UDCA): Ursodeoxycholic Acid (UDCA) is a naturally occurring bile acid that has been used for decades to treat certain liver diseases.

  Researchers became interested in UDCA because of its effects on mitochondria.

  Mitochondria are often called the "power plants" of cells because they generate the energy needed for survival and function.

  In Parkinson's disease, mitochondrial dysfunction is believed to contribute to:

  • Dopamine neuron death

  • Oxidative stress

  • Cellular energy deficits

  • Increased vulnerability to disease progression

  UDCA appears to:

  • Improve mitochondrial function

  • Increase energy production

  • Reduce oxidative stress

  • Protect neurons from programmed cell death

  • Improve cellular resilience

  Early studies have shown promising signals suggesting improved brain energy metabolism and motor function. Mitochondrial dysfunction appears across many forms of Parkinson's disease—not just genetic subtypes—meaning therapies like UDCA could potentially benefit a broad range of patients.

• Istradefylline: Istradefylline is already approved as an adjunct medication for Parkinson's disease in several countries, including the United States.

  Unlike most Parkinson's medications, Istradefylline does not work by increasing dopamine.

  Instead, it blocks adenosine A2A receptors, which influence activity within the basal ganglia—the brain circuits responsible for movement.

  Traditionally, it has been used to reduce "off" time in people taking levodopa.

  However, researchers are now investigating whether its effects may extend beyond symptom management.

  Potential mechanisms include:

  • Modulating abnormal basal ganglia signaling

  • Reducing excessive neural synchrony

  • Influencing neuroinflammatory pathways

  • Supporting healthier neural network function

  While it is not generally viewed as a classic disease-modifying therapy today, researchers are exploring whether long-term effects on neural circuitry could potentially influence disease progression. This is an interesting approach because it targets a completely different pathway than dopamine and may provide insights into how neural network function contributes to Parkinson's progression.

Overall, this platform approach allows researchers to rapidly identify which therapies deserve larger-scale testing. Plus, if one of these drugs do not reach a successful primary endpoint, they can quickly shift to add another drug to the platform and continue where they left off.

P2P Trial

Researchers also discussed the P2P Trial, another innovative effort designed to accelerate therapeutic discovery through more efficient study designs.

Many experts believe platform trials may dramatically shorten the time required to identify effective therapies.

What About a Cure?

One question inevitably comes up whenever new therapies are discussed:

"Are we getting closer to a cure?"

The honest answer is that we still do not know.

No current therapy has definitively demonstrated the ability to stop or reverse Parkinson's disease.

However, something important has changed.

For the first time, researchers are no longer focused solely on replacing dopamine.

They are actively targeting the biological mechanisms driving disease progression.

That represents a major shift in thinking.

The Bigger Picture

One of the strongest themes throughout the World Parkinson Congress was that Parkinson's research is becoming increasingly biological, increasingly personalized, and increasingly hopeful.

Researchers are no longer searching for a single universal treatment.

Instead, they are targeting multiple pathways simultaneously:

• Alpha-synuclein

• Lysosomal dysfunction

• LRRK2 activity

• Mitochondrial dysfunction

• Neuroinflammation

• Genetic risk factors

The future may not be one disease-modifying therapy.

It may be several.

Just as modern cancer care often combines multiple treatments tailored to an individual's biology, Parkinson's care may eventually move toward personalized combinations of therapies matched to specific disease pathways.

We are not there yet.

But after listening to researchers from around the world discuss the current pipeline, it was impossible not to leave with a sense that the field is moving faster than ever before.

And for the first time in decades, the conversation is no longer just about treating symptoms.

It is increasingly about changing the course of the disease itself.

Part 6: Are We Getting Closer to a Cure?

Exploring stem cells, regenerative medicine, cell replacement therapies, and the realistic possibilities—and limitations—of future curative treatments.