Study Rationale: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by pronounced neuroimmune dysfunction. Although the disease is very common, no therapy is available to slow or halt its progression. Emerging evidence suggests that during the early stages of PD, sustained activation of microglia—the immune cells of the brain—may accelerate the aggregation of alpha-synuclein. A cell-surface receptor protein produced predominantly by microglia, called the colony-stimulating factor 1 receptor (CSF1R), appears to be critical for the proliferation and activation of these cells. CSF1R may therefore present an attractive therapeutic target for preventing the inflammation-associated injury of dopamine-producing neurons in PD.
Hypothesis: We hypothesize that early and short-term inhibition of the microglial activation response through blockade of CSF1R via PLX5622 will markedly reduce the neurotoxic effects of microglia-mediated inflammation, thereby diminishing the delayed degeneration of dopamine-producing neurons and the associated neurobehavioral deficits.
Study Design: To further expand on our preliminary findings, we will characterize the effects of PLX5622 administration on the synthesis of CSF1R and the inflammatory activation of microglia in preclinical models of PD. We will determine the full pharmacokinetic profile of PLX5622. Finally, we will investigate the efficacy of PLX5622 treatment in attenuating alpha-synuclein aggregation and the degeneration of dopamine-producing neurons in preclinical models of PD.
Impact on Diagnosis/Treatment of Parkinson’s disease: The successful completion of the proposed studies will advance PLX5622 to clinical development, paving the way towards repurposing the compound as a disease-modifying treatment for PD.
Next Steps for Development: Future plans include applying for grants through the MJFF Therapeutic Pipeline Clinical Program and NIH Blueprint Neurotherapeutics Network or partnering with a pharmaceutical company to pursue clinical testing in people with PD.