LRRK2 in Parkinson disease: challenges of clinical trials
Eduardo Tolosa1,2, Miquel Vila3,4,5, Christine Klein6
1Parkinson and Movement Disorders Unit, Neurology Service, Hospital Clinic of Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Spain. etolosa@clinic.cat.
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.
Insights
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of Parkinson disease (PD). LRRK2 kinase inhibitors show promise for treating PD, including idiopathic forms, by protecting neurons.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a leading cause of monogenic Parkinson disease (PD).
- LRRK2 mutations, including Gly2019Ser, are found in autosomal dominant and sporadic PD cases, clinically resembling idiopathic PD.
- Increased LRRK2 kinase activity due to mutations is linked to PD pathogenesis.
Purpose of the Study:
- To review LRRK2-associated PD characteristics relevant for developing targeted therapies.
- To discuss strategies for LRRK2-targeted therapy development and clinical trial design.
- To explore optimal patient selection and trial timing for LRRK2-based treatments.
Main Methods:
- Review of current literature on LRRK2 genetics, kinase activity, and PD.
- Analysis of preclinical data on LRRK2 kinase inhibitors and neuroprotection.
- Examination of clinical trial designs and challenges for LRRK2-mutated PD.
Main Results:
- LRRK2 kinase inhibitors demonstrate neuroprotective effects in preclinical PD models.
- LRRK2 mutations increase kinase activity, implicating it in PD pathogenesis.
- Evidence suggests LRRK2 plays a role in idiopathic PD, broadening therapeutic potential.
Conclusions:
- LRRK2 is a central target for disease-modifying PD therapies.
- Developing effective LRRK2-targeted treatments requires careful patient stratification and trial design.
- Addressing challenges in clinical trials is crucial for advancing LRRK2-based PD interventions.
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