Disease Modification: Comparing Diverse Approaches to Alpha-Synuclein Targeting Therapies in Parkinson’s Disease

Parkinson's disease (PD) is a prevalent neurodegenerative disorder that mainly affects people over the age of 60.The characteristic movement-related complications, including tremors, akinesia, as well as nonmotor symptoms such as mood disorders, arise when neurodegeneration within the substantia nigra causes a lack of dopamine, creating dysfunction in many systems.A key pathological hallmark of PD is the accumulation of misfolded -synuclein (ASYN), forming toxic aggregates responsible for disease progression.Even with billions spent on healthcare, millions of lives affected, and multiple symptomatic treatments available, there are currently no disease-modifying therapies to slow PD progression.This review compares ten current alpha-synuclein-targeting disease-modifying therapies in clinical trials explored in the Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline: 2023 Update.Because each clinical trial used different biomarkers to prove the slowing neurodegeneration, the drugs were compared on whether they showed a decrease in ASYN aggregates and viability on a cellular level.These therapeutic approaches aimed to reduce pathologic ASYN levels through various mechanisms ranging from antibodies, neurotransmitter regulators, and small molecule therapies.Among them, the small molecule therapies, specifically UCB0599 and Anle-138b, seemed to be the most promising given the greatest blood-brain barrier penetration and decreased pathological alpha-synuclein levels.