Pharmacological Targeting of Inflammation to Modify Disease Progression in Pre-clinical Models of Parkinson’s Disease

Study Rationale:
Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by pronounced brain inflammation. Despite being the most common movement disorder to date, no therapy currently available can slow or halt disease progression. Emerging evidence suggests that, during the early stages of disease, the sustained activation of brain-resident immune cells called microglia may accelerate the accumulation of alpha-synuclein aggregates. Recent studies indicate that a molecule on the surface of microglia, called CSF-1R, plays a critical role in regulating the proliferation of these cells and their involvement in inflammation. Thus, CSF-1R may present a therapeutic target for drugs that can prevent the inflammatory destruction of dopamine-producing neurons in Parkinson’s disease. 

Hypothesis:
We hypothesize that short-term, early inhibition of microglial activation — by blocking CSF-1R — will markedly reduce neurotoxic inflammation and the aggregation of alpha-synuclein, thereby diminishing the death of dopamine-producing neurons and the associated neurobehavioral deficits associated with this neurodegeneration.  

Study Design:
To expand upon our novel preliminary findings, we will characterize how PLX5622, a compound that inhibits CSF1R, affects the inflammation stimulated by microglia in pre-clinical models of PD. We will assess how well the drug is absorbed, metabolized, and excreted, and we will investigate whether PLX5622 successfully minimizes alpha-synuclein accumulation and degeneration of dopamine-producing neurons in pre-clinical models of PD.  

Impact on Diagnosis/Treatment of Parkinson’s Disease:
Completion of the proposed studies will advance PLX5622 to clinical development, thus paving the way toward repurposing this anti-inflammatory compound as a treatment for diminishing the pathological brain changes associated with Parkinson’s disease.

Next Steps for Development:
We plan to apply for grants through the MJFF Therapeutic Pipeline Clinical Program and the NIH Blueprint Neurotherapeutics Network or partner with a pharmaceutical company to conduct clinical testing of PLX5622 in people with Parkinson’s.