LRRK2 in Parkinson disease: challenges of clinical trials

Nat Rev Neurol. 2020 Feb;16(2):97-107. doi: 10.1038/s41582-019-0301-2. Epub 2020 Jan 24.


One of the most common monogenic forms of Parkinson disease (PD) is caused by mutations in the LRRK2 gene that encodes leucine-rich repeat kinase 2 (LRRK2). LRRK2 mutations, and particularly the most common mutation Gly2019Ser, are observed in patients with autosomal dominant PD and in those with apparent sporadic PD, who are clinically indistinguishable from those with idiopathic PD. The discoveries that pathogenic mutations in the LRRK2 gene increase LRRK2 kinase activity and that small-molecule LRRK2 kinase inhibitors can be neuroprotective in preclinical models of PD have placed LRRK2 at the centre of disease modification efforts in PD. Recent investigations also suggest that LRRK2 has a role in the pathogenesis of idiopathic PD and that LRRK2 therapies might, therefore, be beneficial in this common subtype of PD. In this Review, we describe the characteristics of LRRK2-associated PD that are most relevant to the development of LRRK2-targeted therapies and the design and implementation of clinical trials. We highlight strategies for correcting the effects of mutations in the LRRK2 gene, focusing on how to identify which patients are the optimal candidates and how to decide on the timing of such trials. In addition, we discuss challenges in implementing trials of disease-modifying treatment in people who carry LRRK2 mutations.

Publication types

  • Review

MeSH terms

  • Antiparkinson Agents / pharmacology
  • Clinical Trials as Topic
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / drug effects
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics*
  • Parkinson Disease / drug therapy
  • Parkinson Disease / epidemiology
  • Parkinson Disease / genetics*


  • Antiparkinson Agents
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2

Supplementary concepts

  • Parkinson Disease, Familial, Type 1