This project seeks to develop a robust and standardized pre-clinical model relevant to late-onset Parkinson’s disease (PD) that will identify clinically viable LRRK2 kinase inhibitors for the treatment of PD. First, we will determine if LRRK2 knockout rats are protected from rAAV2 alphasynuclein induced dopaminergic neurodegeneration , and if so, whether clinically viable small molecule LRRK2 kinase inhibitors can protect from rAAV2-alpha-synuclein induced dopaminergic neurodegeneration in pre-clinical models.
Many companies and institutes have identified possible LRRK2 inhibitors that have the potential to advance to clinical trial, but pre-clinical animal models with face-validity to late-onset PD poise large technical challenges that hinder their ability to resolve the best compounds.
Here, we propose to use tools developed by MFF and available to all research groups and pharmaceuticals, namely LRRK2 KO models, specific LRRK2 monoclonal antibodies, rAAV2-Alpha-Synuclein virus from UNC, together with the best proprietary LRRK2 kinase inhibitors from Pfizer (see letter of collaboration), to address two fundamental and pressing issues: 1) The role of LRRK2 in alpha-synuclein mediated dopaminergic neurodegeneration, and 2) The development of a valid pre-clinical model for late onset PD (over-expression of alpha-synuclein) that is independent of over-expressed LRRK2 enzyme.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
LRRK2 inhibitors may benefit individuals with G2019S-LRRK2 mutation, individuals at risk for the development of late-onset PD, and individuals already suffering symptoms of PD. Here, we test a historically efficacious platform, namely rAAV2-alpha-synuclein viral induction in pre-clinical models, in the context of LRRK2 acute (small molecule inhibition) and chronic (LRRK2 knockout) activity ablation. These experiments will address a critical void in the drug discovery pipeline, namely relevant pre-clinical models of late-onset disease.
We expect to see robust and reliable dopaminergic degeneration at 8 weeks post viral transduction and expression of alpha-synuclein in the substantia nigra of Long-Evans models, and this degeneration is suppressed in the LRRK2 KO and animals treated with LRRK2 kinase inhibitors.