Study Rationale: Increased neuroinflammation promotes neuron injury and loss (neurodegeneration) and drives progression of Parkinson’s Disease (PD), suggesting that controlling neuroinflammation is an important therapeutic approach in PD. Neuroinflammation is driven by alpha-synuclein aggregates that activate microglia in the brain and recruit inflammatory immune cells from circulation. CD11b is receptor protein that is highly expressed on microglia and on immune cells called monocytes, that is essential for their function. Here, we propose testing a novel compound that selectively targets CD11b in murine models to study if will reduce neuroinflammation and neurodegeneration.
Hypothesis: We have developed a novel compound called LA1 that selectively targets CD11b and reduces recruitment of monocytes into inflamed tissues and their activation, thereby reducing inflammation and tissue damage in inflammatory diseases. We hypothesize that this compound can similarly reduce infiltration of monocytes and activation of microglia, thereby reducing neuroinflammation and neurodegeneration in PD.
Study Design:nWe propose using murine models of PD where the neuroinflammation is driven by viral over-expression of alpha-synuclein protein in the brain. We will administer CD11b agonist LA1 orally in the model systems and examine its efficacy in reducing microglial activation and monocyte recruitment to suppress neuroinflammation and neurodegeneration. We also propose determining brain penetrance of this compound and its pharmacokinetic profile in the brain, in order to fully develop it as a PD therapeutic in the future.
Impact on Diagnosis/Treatment of Parkinson’s disease: Neuroinflammation has been implicated in the early and prodromal phase of PD, suggesting that successful demonstration of efficacy of LA1 in the PD models, as proposed here, will help us translate the findings into improved therapeutics for these phases of PD in patients.
Next Steps for Development: Orally available compound LA1 has successfully completed pre-clinical toxicology studies and is currently being tested in human patients (Phase 1) in oncology, where it has shown good safety profile. This project will allow us to determine its efficacy in Parkinson’s Disease. Successful completion of our proposed project will allow us to plan for clinical testing of this compound as a therapeutic for PD in the near future.