Challenges to the development of disease-modifying therapies in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that involves the neurones of multiple transmitter pathways. The dopaminergic neuronal degeneration determines the main early clinical characteristics of the disease. There have been many recent valuable insights into the pathogenesis of PD, driven primarily by research of the genetic causes of the disease. These now provide a clearer view of the pathways that lead to neuronal dysfunction and death. Perhaps surprisingly, the same pathways initiated by gene mutations causing familial PD are those already identified to be involved in idiopathic sporadic PD, namely mitochondrial dysfunction, oxidative stress and protein misfolding and aggregation. Novel therapies designed to slow PD progression are likely to intervene in one or more of these pathways. Some candidates have been tested based upon this hypothesis, albeit with varying results. Significant developments in this area face several challenges including effective disease-modelling systems and clinical trial designs that can enable a true positive result to be obtained in a relatively short period.