The development of inhibitors of leucine-rich repeat kinase 2 (LRRK2) as a therapeutic strategy for Parkinson's disease: the current state of play

Current therapeutic approaches for Parkinson's disease (PD) are based around treatments that alleviate symptoms but do not slow or prevent disease progression. As such, alternative strategies are needed. A promising approach is the use of molecules that reduce the function of leucine-rich repeat kinase (LRRK2). Gain-of-function mutations in LRRK2 account for a notable proportion of familial Parkinson's disease cases, and significantly, elevated LRRK2 kinase activity is reported in idiopathic Parkinson's disease. Here, we describe progress in finding therapeutically effective LRRK2 inhibitors, summarising studies that range from in vitro experiments to clinical trials. LRRK2 is a complex protein with two enzymatic activities and a myriad of functions. This creates opportunities for a rich variety of strategies and also increases the risk of unintended consequences. We comment on the strength and limitations of the different approaches and conclude that with two molecules under clinical trial and a diversity of alternative options in the pipeline, there is cause for optimism.

Automated summary

Current therapeutic approaches for Parkinson's disease focus on symptom relief rather than disease progression. Inhibition of LRRK2 function is a promising strategy due to its role in familial and idiopathic Parkinson's disease. Progress has been made in finding effective LRRK2 inhibitors, but the complexity of LRRK2 presents challenges and opportunities for unintended consequences. Multiple molecules are in clinical trials, providing cause for optimism in the search for alternative treatment options.