Parkinson’s disease (PD) is a common neurodegenerative movement disorder that currently has no disease-modifying therapies. Over the past two decades, there has been a substantial acceleration in the knowledge of how genetics underlies PD risk. This has given rise to pathological protein targets that can be therapeutically targeted. In particular, there is compelling evidence for developing therapeutic strategies targeting alpha-synuclein, leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GCase). These proteins are implicated in lysosomal function and may contribute to the accumulation of the hallmark pathological forms of alpha-synuclein that define PD. This review highlights current progress on PD therapies targeting these proteins as they attempt to make their way through the clinical trial pipeline, with unique and distinctive approaches being used for each target. Progress is being made in both immunotherapy and small molecule approaches to reduce aggregated forms of alpha-synuclein in the brain, with the aim to stop the propagation of disease. Pathogenic mutations in LRRK2 result in overactivation of the enzyme’s catalytic kinase activity, and consequently kinase inhibitors that aim to reduce LRRK2 activity are in late phase clinical trials. In contrast, PD-associated mutations in GCase generally result in impaired lysosomal GCase activity, and thus small molecule chaperones and allosteric activators of GCase are in advanced development and clinical trials. Although these approaches seem to be generally tolerated by participants in phase I studies, challenges remain in progressing these promising therapies through phase II and beyond.
Nicolas Dzamko (2026) studied this question.