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.
Leucine-rich repeat kinase 2 (LRRK2) has emerged as a promising target for disease-modifying Parkinson disease (PD) treatment because patients with LRRK2-associated PD (LRRK2-PD) constitute a homogeneous subgroup with shared underlying pathophysiology.
Preclinical studies indicate that reduction of LRRK2 activity or expression is neuroprotective; small-molecule LRRK2 inhibitors and antisense oligonucleotides have been developed and are now considered suitable for clinical exposure.
The low penetrance of LRRK2 mutations, a lack of markers that predict conversion to PD and ethical issues preclude implementation of clinical trials in asymptomatic LRRK2 mutation carriers.
Challenges in implementation of disease-modification trials in manifest LRRK2-PD include the low frequency of the condition, a lack of validated disease progression markers and insufficient measures of target engagement.
Clinical trials of specific LRRK2-targeted therapies with a focus on safety have already started, highlighting the rapid progress made over the past decade in LRRK2 research.
LRRK2-PD closely resembles idiopathic PD (iPD), suggesting that unravelling the mechanisms of LRRK2-PD will provide insight into iPD and that LRRK2-targeted therapies could be useful for the treatment of iPD.
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The authors thank H. Madoev for assistance with MDSGene programming and the design of Fig. 1 and C. Perier for the design of Figs 2–4.
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 neuroprotection 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.
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Tolosa, E., Vila, M., Klein, C. et al. LRRK2 in Parkinson disease: challenges of clinical trials. Nat Rev Neurol 16, 97–107 (2020). https://doi.org/10.1038/s41582-019-0301-2
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