Parkinson’s disease (PD) is a progressive neurodegenerative disorder resulting from the loss of dopamine-producing neurons. This loss leads to the well-known motor symptoms of tremor, rigidity, and slowed movement. While existing treatments, mainly based on replacing dopamine or mimicking its effects, have offered significant relief for decades, they do not stop the underlying disease progression. Current research is intensely focused on developing therapies that not only improve symptom control but also create novel treatments that can slow or even halt the neurodegenerative process itself.
Refining Motor Symptom Management
New advancements are largely focused on delivering existing medications more smoothly or employing less invasive surgical techniques to manage the physical symptoms of PD. The challenge with standard oral levodopa is that its effect can fluctuate throughout the day, leading to periods where symptoms are poorly controlled, known as “off” time. To counteract this, new formulations and delivery systems have been developed to ensure a more consistent level of medication in the body.
New drug formulations include an extended-release oral capsule that combines immediate- and prolonged-release levodopa to smooth out the therapeutic effect, and a subcutaneous infusion pump that delivers a continuous flow of a levodopa prodrug under the skin over 24 hours. This continuous delivery system is a significant step forward for advanced PD patients who experience severe motor fluctuations and troublesome “off” periods.
Surgical treatments are also becoming more refined, particularly Deep Brain Stimulation (DBS). Modern DBS systems now feature directional leads, which allow the electrical stimulation to be steered toward a precise target within the brain, potentially enhancing symptom relief while minimizing side effects. A particularly recent innovation is adaptive DBS, a closed-loop system that senses brain signals in real-time and automatically adjusts the stimulation only when needed, which is a major advance over continuous stimulation models.
A less invasive alternative to DBS is Magnetic Resonance-guided Focused Ultrasound (MRgFUS), which uses high-intensity sound waves to precisely ablate a small area of the brain responsible for tremor without requiring any surgical incision. This incisionless option provides a promising, lower-risk procedure for individuals whose primary burden is tremor. Furthermore, low-intensity focused ultrasound is being explored for its ability to temporarily open the blood-brain barrier, which could enhance the delivery of larger drug molecules to the brain that normally cannot pass this protective layer.
Disease-Modifying Therapies
The most profound area of research is the pursuit of treatments that address the root causes of Parkinson’s disease, offering the potential to slow or stop its progression. The defining characteristic of PD is the accumulation of a misfolded protein called alpha-synuclein, which clumps together to form Lewy bodies, causing toxicity in neurons. Immunotherapy is a strategy that aims to clear these toxic clumps, using either passive immunization—infusing manufactured antibodies—or active immunization, which involves a vaccine-like approach to encourage the patient’s own body to produce antibodies against the protein.
One of the most advanced examples of this approach is prasinezumab, a monoclonal antibody that targets alpha-synuclein and is currently progressing into late-stage clinical trials. Another biological strategy involves gene therapy, which aims to deliver genetic material directly to brain cells to restore function or provide protection. Approaches include using a harmless virus to deliver genes that help neurons synthesize dopamine or genes that code for neuroprotective growth factors, such as Glial Cell Line-Derived Neurotrophic Factor (GDNF), to support the survival of remaining neurons.
Researchers are also exploring small molecules that target other biological processes implicated in PD, such as mitochondrial dysfunction and neuroinflammation. For example, some molecules are designed to boost the activity of the enzyme glucocerebrosidase (GCase). Since a genetic mutation in the GBA gene, which codes for GCase, is a common risk factor for PD, enhancing its function with repurposed drugs like ambroxol is a promising strategy to improve the clearance of alpha-synuclein aggregates. The diversity of targets underscores the growing understanding that PD is a complex disorder with multiple underlying pathologies beyond just dopamine loss.
Emerging Focus on Non-Motor Symptoms
While motor symptoms are the most visible manifestation of Parkinson’s, non-motor symptoms like cognitive impairment, mood disorders, and autonomic dysfunction often have a greater impact on quality of life, leading to targeted drug development for these specific issues. For PD-related psychosis, which includes hallucinations and delusions, newer medications that act on serotonin receptors, such as pimavanserin, have shown to be effective without worsening motor symptoms, which is a common side effect of older antipsychotics.
Cognitive difficulties, including mild cognitive impairment and dementia, are being addressed with drugs that modulate the activity of NMDA receptors. This is an attempt to go beyond the mildly effective approved medications currently available for PD dementia. Furthermore, neurogenic orthostatic hypotension (NOH), a condition that causes a sudden drop in blood pressure upon standing, leading to dizziness and fainting, is a major focus.
New treatments and repurposed drugs are being investigated to improve blood pressure regulation in NOH. Sleep disorders, such as excessive daytime sleepiness and REM sleep behavior disorder, are also receiving attention, with clinical trials exploring new compounds to promote wakefulness or regulate sleep cycles. This dedicated focus on non-motor symptoms recognizes that truly holistic care for PD requires managing the full spectrum of the disease’s effects on the body and mind.
Navigating Clinical Trials and Timelines
The promising therapies described are currently at various stages of the rigorous clinical trial process necessary before they can be widely available. This process is divided into phases: Phase 1 trials focus on safety and dosage; Phase 2 evaluates effectiveness and side effects in a larger cohort; and Phase 3 trials involve thousands of people, comparing the new treatment against a standard treatment or placebo to confirm its overall benefit.
The transition from a Phase 2 trial to a Phase 3 trial, particularly for disease-modifying agents, remains a significant hurdle in the PD research community, reflecting the complexity of slowing a neurodegenerative process. Even with encouraging Phase 2 results, a drug typically requires several years of Phase 3 testing to demonstrate a meaningful effect on disease progression.
While new symptomatic treatments or device refinements often gain regulatory approval within a few years of late-stage trials, novel disease-modifying therapies are likely five to ten years away from becoming standard care. Patient involvement in clinical trials is the only way to accelerate the timeline for these breakthroughs. While participating in a trial carries risks, it offers the opportunity to access cutting-edge treatments and contribute to the scientific understanding of the disease.