| Attribute | Value | [1]
|-----------|-------| [2]
| Category | Disease-Modifying Therapy | [3]
| Target | LRRK2 (Leucine-Rich Repeat Kinase 2) | [4]
| Diseases | Parkinson's Disease | [5]
| Development Stage | Phase I-II Clinical Trials | [6]
| Route | Oral | [7]
LRRK2 (leucine-rich repeat kinase 2) is the most common genetic cause of Parkinson's disease, with mutations in the LRRK2 gene (particularly G2019S) causing approximately 5-10% of familial PD and 1-2% of sporadic PD cases. LRRK2 is a large multi-domain protein with GTPase and kinase activities that regulates various cellular processes including: [8]
LRRK2 inhibitors work by:
| Drug | Company | Stage |
|---|---|---|
| G007-LK | Genentech | Preclinical |
| LRRK2-IN-1 | Various | Research |
LRRK2 (Leucine-Rich Repeat Kinase 2) is a large 2527-amino acid protein with multiple functional domains:
Wild-type LRRK2 is involved in:
Over 50 LRRK2 mutations cause familial Parkinson's disease:
| Mutation | Domain | Effect |
|---|---|---|
| G2019S | Kinase | Increased kinase activity |
| R1441C/G/H | ROC | Reduced GTPase activity |
| Y1699C | COR | Altered protein interactions |
| I2020T | Kinase | Increased autophosphorylation |
The G2019S mutation (most common) increases kinase activity by ~40%, leading to:
Key considerations for LRRK2 inhibitor trials:
Primary endpoints
Secondary endpoints
| Company | Drug | Mechanism | Stage |
|---|---|---|---|
| Denali/Dietsmann | DNL151/Lunagrelpar | LRRK2 inhibitor | Phase II |
| Biogen | BIIB122 | LRRK2 inhibitor | Phase II |
| Genentech | G008-LK | LRRK2 inhibitor | Preclinical |
| Bristol Myers | BMS-986202 | LRRK2 inhibitor | Phase I |
The study of Lrrk2 Inhibitors For Parkinson'S Disease has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
Cookson MR (2015) LRRK2 and Parkinson's disease. Nature Reviews Neuroscience. 2015. ↩︎
Rideout HJ, Reimer J (2020) LRRK2-targeting small molecule inhibitors. Neurobiology of Disease. 2020. ↩︎
Tolosa E, et al. (2020) LRRK2 in Parkinson disease: Challenges and opportunities. Nature Reviews Neurology. 2020. ↩︎
Alessi DR, Sammler E (2018) LRRK2 kinase in Parkinson's disease. Science. 2018. ↩︎
Bonet-Ponce L, Cookson MR (2019) LRRK2 and autophagy in Parkinson's disease. Current Opinion in Neurobiology. 2019. ↩︎
Di Maio R, et al. (2018) LRRK2 dysfunction in vivo produces progressive parkinsonism. Brain. 2018. ↩︎
Wallings R, et al. (2019) LRRK2 and neuroinflammation. Journal of Neural Transmission. 2019. ↩︎
Taymans JM, Greggio E (2016) LRRK2 in Parkinson's disease: Biochemical functions. FEBS Journal. 2016. ↩︎