Objective/Rationale:
Parkinson’s disease (PD) involves inappropriate activation of the immune system. Cytokines activate immune cells by engaging the JAK/STAT pathway, which receives signals from cytokines, and transmits them to cells. PD is associated with elevated levels of cytokines that activate the JAK/STAT pathway. We propose that the JAK/STAT pathway is inappropriately activated in PD, which leads to neuroinflammation and neuronal damage, and that inhibition of the JAK/STAT pathway will be of benefit to PD patients.
Project Description:
AZD1480 is an inhibitor of JAK1 and JAK2, and inhibits activation of downstream STAT proteins. The AAV2-SYN model will be used to test the anti-inflammatory and neuroprotective effects of AZD1480, looking at: 1) DA neuron survival; 2) extent of JAK1/2 and STAT inhibition in the brain to determine if the target is engaged effectively; and 3) effects on neuroinflammatory events in the brain. The AAV2-SYN pre-clinical model is characterized by activation of the immune system at four weeks, with neurodegeneration with significant DA neuronal loss at 12 weeks. The pre-clinical models will be stereotaxically injected with a virus overexpressing human alpha synuclein (AAV2-SYN) or green fluorescent protein (AAV2-GFP) as control over the left SN. Neuroinflammatory changes and JAK/STAT signaling status will be tested at four weeks and neurodegeneration at 12 weeks.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
These findings will establish “proof of concept” for the use of pharmacological inhibitors of the JAK/STAT pathway in human PD. Confirmation of the ability of AZD1480 to have a beneficial impact in models of PD will validate the JAK/STAT pathway as a target for PD therapeutics. These small molecule inhibitors have a good safety profile, furthering the rationale for their clinical application in neurodegenerative diseases such as PD.
Anticipated Outcome:
These pre-clinical translational studies in models of PD will inform us of the validity of targeting the JAK/STAT pathway for abrogation of neuroinflammatory responses and neuronal damage, and indicate if further research in this area is warranted. JAK inhibitors are in clinical trials for other indications (cancer, rheumatoid arthritis), are well tolerated, orally available and do not promote immunosuppression. We are hopeful that JAK inhibitors will represent a new treatment modality for PD patients in the future.
Final Outcome
Our results indicate that the signaling pathway known as JAK/STAT, is over-activated in a pre-clinical model of Parkinson’s disease. We believe this over-activation contributes in a significant manner to the neuroinflammatory response observed in this model at four weeks, and to the neurodegenerative response observed at 12 weeks. Using a pharmacological inhibitor of the JAK/STAT pathway, the neuroinflammatory and neurodegenerative responses were significantly suppressed, compared to models that received a control treatment. We propose that the use of inhibitors of the JAK/STAT pathway may be of therapeutic benefit for patients with PD.