Approaches to Disease Modification for Parkinson's Disease: Clinical Trials and Lessons Learned.

Despite many clinical trials over the last three decades, the goal of demonstrating that a treatment slows the progression of Parkinson's disease (PD) remains elusive. Research advances have shed new insight into cellular pathways contributing to PD pathogenesis and offer increasingly compelling therapeutic targets. Here we review recent and ongoing clinical trials employing novel strategies toward disease modification, including those targeting alpha-synuclein and those repurposing drugs approved for other indications. Active and passive immunotherapy approaches are being studied with the goal to modify the spread of alpha-synuclein pathology in the brain. Classes of currently available drugs that have been proposed to have potential disease-modifying effects for PD include calcium channel blockers, antioxidants, anti-inflammatory agents, iron-chelating agents, glucagon-like peptide 1 agonists, and cAbl tyrosine kinase inhibitors. The mechanistic diversity of these treatments offers hope, but to date, results from these trials have been disappointing. Nevertheless, they provide useful lessons in guiding future therapeutic development.