Status and future directions of clinical trials in Parkinson's disease.

Novel therapies are needed to treat Parkinson's disease (PD) in which the clinical unmet need is pressing. Currently, no clinically available therapeutic strategy can either retard or reverse PD or repair its pathological consequences. l-DOPA (levodopa) is still the gold standard therapy for motor symptoms yet symptomatic therapies for both motor and non-motor symptoms are improving. Many on-going, intervention trials cover a broad range of targets, including cell replacement and gene therapy approaches, quality of life improving technologies, and disease-modifying strategies (e.g., controlling aberrant α-synuclein accumulation and regulating cellular/neuronal bioenergetics). Notably, the repurposing of glucagon-like peptide-1 analogues with potential disease-modifying effects based on metabolic pathology associated with PD has been promising. Nevertheless, there is a clear need for improved therapeutic and diagnostic options, disease progression tracking and patient stratification capabilities to deliver personalized treatment and optimize trial design. This review discusses some of the risk factors and consequent pathology associated with PD and particularly the metabolic aspects of PD, novel therapies targeting these pathologies (e.g., mitochondrial and lysosomal dysfunction, oxidative stress, and inflammation/neuroinflammation), including the repurposing of metabolic therapies, and unmet needs as potential drivers for future clinical trials and research in PD.