Study Rationale: Inhibitors of the LRRK2 protein offer promise as a therapy for Parkinson’s disease (PD). The leading inhibitors currently under development, the so-called Type 1 kinase inhibitors, work by reducing LRRK2 kinase activity to healthy levels. Recent preclinical studies have shown that Type 1 inhibitors can cause lung toxicities, raising the question as to whether similar reactions will occur in people with PD upon prolonged drug treatment. A safer alternative may be a non-Type 1 inhibitor, which will still inhibit LRRK2 while potentially avoiding any related lung toxicities.
Hypothesis: We hypothesize that Type 1 LRRK2 inhibitors cause changes to the lung by obstructing crucial transport mechanisms within lung cells. Non-Type 1 inhibitors do not affect these transporters in the same way, giving them the potential to treat PD without causing adverse lung toxicities.
Study Design: First, we will develop non-Type 1 inhibitors that are potent, selective and can penetrate into the brain. Then, using those inhibitors, we plan to conduct a safety assessment in cells and in preclinical animal models to characterize any adverse findings. We can then compare the reported results for Type 1 inhibitors with those generated for our new non-Type 1 inhibitors to assess the relationship between the inhibitor type and lung toxicity.
Impact on Diagnosis/Treatment of Parkinson’s disease: Through this study, we hope to develop a safe therapeutic for chronically administration in people with PD that has no negative consequences on lung function.
Next Steps for Development: This investigation may provide supporting information for the ongoing development of non-Type 1 inhibitors past preclinical trials and into human trials.