Study Rationale:
LRRK2 is expressed in immune cells but its function in these cells is unknown. It is also not known whether mutations (such as G2019S) in LRRK2 that cause familial (inherited) Parkinson's disease (PD) affect immune cell function. Given that LRRK2 inhibitors are being developed for clinical trials in PD, it is critical that the role of normal and mutant LRRK2 in immune cells be clearly established. Additionally, it is important to understand the effects of LRRK2 therapeutic inhibition on immune cell function so that side effects (if any) of such treatment on the immune system can be avoided. The role of wild-type and mutant LRRK2, as well as that of specific inhibitors on immune cell function, will be tested in model systems.
Hypothesis:
Due to the increased enzymatic activity associated with LRRK2 mutants, such as G2019S, we hypothesize that LRRK2 G2019S will lead to a gain of function of immune cell activity and that this activity will manifest itself in changes in the ability of the immune system to respond to infection. We further hypothesize that inhibition of enzymatic activity may affect the responses of wild-type immune cells as well.
Study Design:
Since human immune cells are the primary cellular targets of interest, we will use primary human immune cells from healthy participants and participants with PD (some of who will carry LRRK2 G2019S mutations) treated with LRRK2 kinase inhibitors. To determine the effects of LRRK2 kinase inhibitor treatment, we will complement the studies of human cells with studies in pre-clinical models.
Impact on Diagnosis/Treatment of Parkinson's Disease:
A better understanding of the role of LRRK2 in immune cells is expected to reveal ways in which altered LRRK2 function may contribute to disease risk or progression. In addition, these studies may reveal any potential beneficial (or harmful) effects that therapeutic use of LRRK2 kinase inhibitors may have on human immune function. These studies will help develop safer and more efficacious clinical trial outcomes.
Next Steps for Development:
If we find that LRRK2 is critical for the function of all or specific subsets of immune cells, development of therapeutic interventions to alter LRRK2 levels or function will need to proceed with extreme caution to avoid damage to the immune system. If immune cell function is found to be negatively impacted by LRRK2 G2019S mutations, therapeutic use of LRRK2 kinase inhibitors is likely to positively impact the effect of such mutations and lower risk for PD or disease progression