Study Rationale: Mutations in LRRK2 are thought to be causative for Parkinson’s disease (PD), but increases in LRRK2 activity have also been observed in non-familial cases of PD. As a result, LRRK2 inhibitors have been developed to treat this subset of people with PD. However, many LRRK2 inhibitors can cause irreversible kidney and lung toxicity, which limits our ability to target LRRK2. To treat PD without causing lung or kidney damage, we aim to develop an inhibitor that specifically targets LRRK2 in the brain.
Hypothesis: LRRK2 is expressed in and essential to the proper functioning of various tissues. Because LRRK2 hyperactivity is thought to interfere with proper neuronal functioning, we hypothesize that specifically inhibiting LRRK2 in the brain will allow us to treat PD without interfering with its proper function in other tissues, thus avoiding toxicity.
Study Design: We have developed a technology by which we can specifically inhibit LRRK2 in the brain. We will adapt existing LRRK2 inhibitors to our BrainOnly technology. We will test whether our new BrainOnly LRRK2 inhibitors inhibit LRRK2 in the brains of mice and rats without inhibiting LRRK2 in the lungs or kidneys. We will then compare the lung and kidney toxicity of previously reported LRRK2 inhibitors with our BrainOnly LRRK2 inhibitors in animals to determine whether they are safer than current generation LRRK2 inhibitors, which require careful monitoring in the clinic.
Impact on Diagnosis/Treatment of Parkinson’s Disease: Physicians must carefully monitor individuals receiving LRRK2 inhibitors, limiting the number of people receiving the drug. Toxicities also limit the dose of the inhibitor, which may reduce its efficacy. BrainOnly LRRK2 inhibition could allow physicians to give higher doses to a broader patient population without concerns about safety.
Next Steps for Development: Upon study completion, we will understand the relative safety and efficacy of BrainOnly LRRK2 inhibitors in preclinical models. We will then apply for authorization to begin dosing healthy volunteers and people with PD with the BrainOnly LRRK2 inhibitor.