Study Rationale: Inflammation in the brain promotes neurodegeneration and drives the progression of Parkinson’s disease (PD), suggesting that controlling neuroinflammation could provide an important therapeutic approach in PD. Neuroinflammation is driven by the accumulation of alpha-synuclein aggregates, which activates the brain’s resident immune cells, called microglia, and recruits inflammatory immune cells, called monocytes, from circulation. CD11b is receptor protein that is present in large numbers on microglia and monocytes, and is essential for their function. Here, we propose testing a novel compound that selectively targets CD11b in preclinical mouse models of PD to assess its ability to reduce neuroinflammation and neurodegeneration.
Hypothesis: We have developed a novel compound, LA1, that targets CD11b and reduces the infiltration and activation of monocytes in inflamed tissues, thereby reducing 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: We will administer LA1 orally in preclinical mouse models of PD in which neuroinflammation is driven by overproduction of alpha-synuclein protein in the brain. We will examine how effective this compound is in suppressing neuroinflammation and neurodegeneration by reducing microglial activation and monocyte recruitment. We will also determine how well the compound penetrates the brain and assess how it is absorbed, distributed, localized and metabolized there. This pharmacokinetic profile will allow us to fully develop LA1 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 proposed here will help us translate the findings into improved therapeutics for these phases of the disorder in people with PD.
Next Steps for Development: Orally available LA1 has completed preclinical toxicology studies and has shown a good safety profile in Phase 1 trials in oncology. This project will allow us to determine its efficacy in PD and to plan for clinical testing of this compound as a PD therapeutic in the near future.