Understanding of Parkinson's has grown substantially over the past two decades. The Michael J. Fox Foundation is building on this momentum to explore prevention of the disease and transform diagnosis and treatments.
Years of work spent uncovering Parkinson’s secrets — defining the highly variable patient experience, shedding light on genetic origins of disease, mapping molecular pathways — are now paying off in a tangible quickening tempo of scientific progress. Investigators are increasingly linking cellular pathology to outward clinical symptoms (and vice versa) to identify new therapeutic and biomarker targets. This has positioned drug makers to make rapid inroads toward treatments that have the potential to slow or stop progression of Parkinson's disease (PD). The field also is closer than ever to arriving at therapies that can treat all the symptoms of PD, including the less well understood non-motor aspects, such as cognitive impairment and mood disorders, sleeping and digestive issues, and speech and swallowing difficulties.
While the Parkinson's pipeline is more active than at any previous point in the modern era of drug development, much work remains to be done in the quest to better understand the connection between pathological "bad actors" and the daily lived experience of the disease — and to translate understanding of basic Parkinson's biology into new therapies.
Parkinson's Disease Understanding
In stark contrast to the Parkinson's research field of just a few years ago, several therapies — mostly due to increased understanding of Parkinson's genetics — are now in clinical trials. While therapies based on genetic understanding may benefit the broad disease population over time, early clinical trials are taking a precision-medicine approach, recruiting participants based on individual biology.
Scientists believe the following approaches are currently closest to translation into practical therapies that may slow or stop Parkinson’s disease — something no current therapy has been demonstrated to do:
- GBA mutations, also linked to Gaucher disease, are the most common genetic cause of PD yet discovered, accounting for five to 15 percent of all Parkinson’s cases, depending on ethnicity. Counteracting the dysfunction associated with GBA mutations — lowered activity of the glucocerebrosidase (GCase) protein — could slow or stop progression of Parkinson’s disease.
- The genetic target LRRK2 has been the focus of intense investigation by PD researchers since its discovery in 2004. The first in-human trials of LRRK2 inhibitors started in 2017. Work is ongoing to provide insight into unknown aspects of LRRK2 biology and better target experimental therapies against it.
- A universal feature of Parkinson’s is aggregation, or clumping, of the protein alpha-synuclein in the brains and body cells of people with the disease (similar to the amyloid clumps seen in Alzheimer’s disease). Multiple drug companies are conducting clinical trials to try to prevent or break up synuclein clumps, which scientists believe could stop PD in its tracks. Therapeutic development is expected to accelerate as clinical trials integrate new biomarker testing for this Parkinson's form of alpha-synuclein.
- Several potentially disease-modifying therapies continue to advance via “repurposing” — scientifically evaluating drugs approved for various conditions for their benefit in PD. Isradipine (a hypertension drug) and inosine (an antioxidant supplement) are now in Phase III trials. The field also has seen promise in the diabetes drug exenatide and the cancer drug nilotinib.
The Search for an Objective Test
The need for objective Parkinson’s disease tests, or biomarkers (like hypertension in heart disease or blood sugar levels in diabetes), has become more urgent as more projects enter human testing. Objective disease tests would speed drug development by identifying people most likely to respond to treatment, tracking disease progression and assessing therapeutic impact.
The Parkinson's Progression Markers Initiative (PPMI) is the Foundation’s landmark public-private partnership to identify and validate biomarker candidates and develop tests to selectively and specifically measure Parkinson’s pathology and symptoms. PPMI has become a world model for Parkinson’s study design, lending the field groundbreaking tools and insights such as the use of dopamine scans (DaTscan) as an early PD progression marker, the identification of factors that may predict cognitive decline, and even best practices in how to effectively recruit patients and controls for clinical studies — an ongoing challenge in Parkinson’s research. PPMI played a pivotal role in the breakthrough discovery in 2023 of a biomarker test for Parkinson’s, called the alpha-synuclein seeding amplification assay. The test makes it possible for the first time to diagnose Parkinson’s biologically, even before symptoms begin.
Work is ongoing in pursuit of advanced brain imaging tracers that would allow scientists to visualize key cellular entities in the living brain. A similar tracer has been fundamental to recent progress in Alzheimer's therapeutic development and holds potential to transform diagnosis, track disease and provide therapeutic assessment in people with Parkinson's as well as atypical parkinsonisms such as Lewy body dementia (LBD) and progressive supranuclear palsy (PSP).
From Biology to New Therapies
While seven new Parkinson’s drugs have come to market since 2014 — a heartening expansion of treatment options — scientists continue working aggressively on many fronts toward next-generation therapies to greatly improve the treatment and management of motor and non-motor symptoms. These projects require, in tandem, funding, objective biological measures, infrastructure to support recruitment, and coordination with regulators and payers.
Several novel formulations of levodopa are currently anticipated to receive regulatory approval in the near future. These include inhaled and transdermal formulations backed and "de-risked" by The Michael J. Fox Foundation (MJFF) in early development. An improved delivery of levodopa has been a primary field goal for years, as scientists have searched for a more consistent way to get the drug into the brain. When taken orally, absorption of the traditional oral formulation into the blood and brain can be inconsistent, coming in peaks and valleys, which is believed to lead to motor fluctuations, including disabling “off” periods.
While no longer considered the "silver bullet" scientists once hoped, stem cell approaches continue advancing toward therapeutic relevance. Induced pluripotent stem cells (also known as iPS cells — engineered by reprogramming mature adult cells) are expected to one day treat motor symptoms by replacing damaged dopamine cells.
Deep brain stimulation (DBS) surgery, while already available and appropriate for some patients, remains under active study to expand its benefits to a wider range of individuals with Parkinson’s disease. One ongoing investigation seeks to target brain areas associated with balance problems (unaddressed by current forms of DBS). Another team wants to determine whether DBS can slow symptom progression if administered in earlier stages of disease. Others are working to develop adaptive or “intelligent” DBS — allowing for the continuous optimization of therapy on an individual basis, maximizing motor symptom improvement and minimizing adverse effect, prolonging battery life and reducing the need for battery replacement surgeries.