Abstract
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.
| Original language | English |
|---|---|
| Journal | Nature Reviews Neurology |
| Volume | 16 |
| Issue number | 2 |
| Pages (from-to) | 97-107 |
| Number of pages | 11 |
| ISSN | 1759-4758 |
| DOIs | |
| Publication status | Published - 01.02.2020 |
Funding
E.T. has received research grants from the Spanish Network on Neurodegenerative Disorders (CIBERNED, Instituto de Salud Carlos III) and the Michael J. Fox Foundation for Parkinson’s Research (USA), and has received consultation fees from Denali Therapeutics. M.V. has received research grants from the Ministry of Economy and Competitiveness (MINECO, Spain), the Michael J. Fox Foundation for Parkinson’s Research (USA) and La Caixa Banking Foundation (Spain). C.K. is a medical adviser to CENTOGENE for genetic testing reports in the fields of movement disorders and dementia, excluding Parkinson disease. O.R. has received honorarium for scientific advice to companies developing neuroprotective therapies for Parkinson disease, including Biogen, Cerespir, Denali Therapeutics, Roche and Sanofi. O.R. has received grants for research programmes in neuroprotec-tion for Parkinson disease from the French Ministry of Health (Programme Hospitalier de Recherche Clinique), The European Commission (FP7, H2020 programmes) and the Cure Parkinson UK Foundation.
Research Areas and Centers
- Research Area: Medical Genetics
