This commentary proposes evaluating rationally designed combination therapies that target multiple Parkinson's disease etiological factors as an alternative strategy to discover disease-modifying treatments.

While it presents no new experimental data, the paper shifts emphasis toward combination approaches that could enhance translational and repurposing potential by addressing complementary mechanisms and informing future trial design.

Despite significant advances in our understanding of Parkinson's disease (PD) over the last three decades, no disease-modifying therapies (DMTs) have been identified. There is considerable effort focused on this goal, but the challenges in achieving it are illustrated by the limited number of DMTs advancing to late-stage Phase 3 clinical testing (see annual Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline publications). The lack of progress towards slowing the disease is further highlighted by the recent disappointing results from high profile, Phase 2/3 clinical trials for DMTs. In this commentary, we would like to suggest an alternative strategy for identifying DMTs. Specifically, we propose the evaluation of rationally designed combination therapies that target multiple PD etiological factors.