Disease modifying therapies III: Novel targets

Despite significant research advances, treatment of Parkinson's disease (PD) remains confined to symptomatic therapies. Approaches aiming to halt or reverse disease progression remain an important but unmet goal. A growing understanding of disease pathogenesis and the identification of novel pathways contributing to initiation of neurodegeneration and subsequent progression has highlighted a range of potential novel targets for intervention that may influence the rate of progression of the disease process. Exploiting techniques to stratify patients according to these targets alongside using them as biomarkers to measure target engagement will likely improve patient selection and preliminary outcome measurements in clinical trials. In this review, we summarize a number of PD-related mechanisms that have recently gained interest such as neuroinflammation, lysosomal dysfunction and insulin resistance, while also exploring the potential for targeting peripheral interfaces such as the gastrointestinal tract and its ecosystem to achieve disease modification. We explore the rationale for these approaches based on preclinical studies, while also highlighting the status of relevant clinical trials as well as the promising role biomarkers may play in current and future studies.