GBA1-and LRRK2-directed Treatments: The Way Forward

• Published in: Parkinsonism & related disorders 2024-05, Vol.122, p.106039-106039, Article 106039
• Main Authors: Maayan Eshed, Gadi, Alcalay, Roy N.
• Format: Article
• Language: English
• Subjects: Animals; Glucosylceramidase - genetics; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics; Mutation; Parkinson Disease - drug therapy; Parkinson Disease - genetics
• ISSN: 1353-8020; 1873-5126
• DOI: 10.1016/j.parkreldis.2024.106039

There is an urgent need to identify drug targets for disease modification in Parkinson's Disease (PD). In this mini-review we highlight the reasons genetically-defined drug targets show great promise. Specifically, clinical trials targeting the glucocerebrosidase-1 (GBA1) and leucine-rich repeat kinase 2 (LRRK2) genes are underway. Two key knowledge gaps are 1. How should we modify the GBA1 and LRRK2 pathways? and 2. Which patient populations are most likely to benefit? The exact mechanisms by which mutations in these genes cause PD are not fully understood. Most drugs targeting the GBA1 pathway in clinical trials aim at increasing glucocerebrosidase enzymatic (GCase) activity and targeting the LRRK2 pathway, at reducing its kinase activity. Carriers of mutations in these genes are natural candidates for such interventions; however, there are some biomarker data, specifically for GBA1, to support studying such interventions in non-carriers, i.e., sporadic PD. In summary, we anticipate significant progress in our path towards precision medicine in PD in the coming years. •The GBA1 and LRRK2 pathways are promising targets for Parkinson's Disease treatment for mutation carriers.•Most studies of intervention in the GBA1 pathway aim to increase glucocerebrosidase enzymatic (GCase) activity.•Most studies of intervention in the LRRK2 pathway aim to reduce the kinase activity of LRRK2.•Clinical trials studying the potential benefit of these interventions in both carriers and non-carriers are underway.