Targeted Therapies for Parkinson's Disease: From Genetics to the Clinic

Abstract

The greatest unmet medical need in Parkinson's disease (PD) is treatments that slow the relentless progression of symptoms. The discovery of genetic variants causing and/or increasing the risk for PD has provided the field with a new arsenal of potential therapies ready to be tested in clinical trials. We highlight 3 of the genetic discoveries (α-synuclein, glucocerebrosidase, and leucine-rich repeat kinase) that have prompted new therapeutic approaches now entering the clinical stages. We are at an exciting juncture in the journey to developing disease-modifying treatments based on knowledge of PD genetics and pathology. This review focuses on therapeutic paradigms that are under clinical development and highlights a wide range of key outstanding questions in PD. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Keywords: GBA LRRK2; SNCA; clinical trial; glucocerebrosidase; α-synuclein.

Figure 1

Potential mechanisms for genetic‐based investigational therapies for Parkinson's disease targeting α‐synuclein (SNCA), glucocerebrosidase (GBA), and leucine‐rich repeat kinase (LRRK2). Targeting SNCA: (1) reducing α‐synuclein production, (2) decreasing α‐synuclein aggregation, (3) enhancing autophagy, (4) reducing availability of extracellular aggregates, (5) inhibiting cellular uptake of α‐synuclein. Targeting the GBA pathway: (6) increasing glucocerebrosidase (GCase) activity, (7) modulating GBA‐related glycosphingolipids. Targeting LRRK2: (8) LRRK2 kinase inhibitors.