Objective/Rationale:
One of the hallmark pathologies in the brains of patients with Parkinson’s disease (PD) is an inflammatory response. We will test whether the cytokine interleukin-10 (IL-10), capable of dampening inflammatory responses, may prolong lifespan in pre-clinical models that recapitulate the major protein inclusion pathology in human PD. These transformative studies could provide pivotal data needed to identify novel disease-modifying therapeutic approaches that target the immune system in PD.
Project Description:
In trying to broadly suppress proinflammatory innate immune activation in various neurodegenerative pre-clinical models, we have identified chronic IL-10 expression as a well-tolerated and effective way to suppress the proinflammatory phenotypes. We will use viral methods to deliver the anti-inflammatory cytokine IL-10 to the central nervous system of a transgenic pre-clinical model of neurodegeneration-induced mutant alpha-synuclein expression. As these models age, they develop alpha-synuclein pathology reminiscent of the Lewy Body pathology seen in humans with PD, and shortly thereafter develop a severe motor phenotype. The main endpoint will be whether we delay the time to onset of the motor phenotype in these models by expression of IL-10. We will also closely monitor how IL-10 alters inflammation in this model.
Relevance to Diagnosis/Treatment of Parkinson’s disease:
IL-10 has been tested in humans for a variety of autoimmune disorders. If IL-10 proves to be disease-modifying, this would provide preclinical validation of anti-inflammatory approaches to PD. IL-10 could be further developed as a PD therapeutic in its own right, but because it is a biologic agent, we would suggest that this study also open the door to multiple lines of therapeutically oriented research to evaluate a variety of potential anti-inflammatory strategies in PD.
Anticipated Outcome:
We are testing the hypothesis that IL-10 will be protective in a model of neurodegeneration induced by alpha-synuclein that is highly relevant to human PD. We predict that IL-10 will be protective. However, the precise role of inflammation in PD and other neurodegenerative disorders remains enigmatic. Thus, other outcomes including accelerating disease in this model are possible, but nevertheless will be informative.
Final Outcome
The immune system is one of the key contributors to Parkinson's disease (PD). In this study, we explored whether altering the immune system in a pre-clinical model of alpha-synuclein pathology would have a therapeutic benefit. Specifically, we evaluated whether increased levels of the IL-10 cytokine -- a chemical produced by immune cells to suppress inflammation -- would ameliorate disease progression. In contrast to our expectations, IL-10 decreased survival in this model. These data indicate that it is difficult to accurately predict whether manipulating the immune system is beneficial in PD. Hence, research studies will be needed to develop immune therapies for Parkinson's disease. Notably, our studies confirmed the potential usefulness of this induced model of alpha-synuclein pathology for pre-clinical testing of therapies. Future studies will explore whether decreasing IL-10 signaling -- chemical reactions inside the cells triggered by IL-10 -- would have a therapeutic benefit, as our current results suggest.
April 2016