Modulation of the CD40/CD40-Ligand Neuroinflammation Pathway in Parkinson's Pre-Clinical Models
Rapid Response Innovation Awards, 2012
In PD and PD-related models, neuroinflammation has been well documented. However, it is still unknown if neuroinflammation is a cause, contributor, or bystander in PD-linked degeneration of dopaminergic neurons. Looking at specific neuroinflammation pathways may answer this question. We think the activation of the CD40-CD40L pathway contributes to PD disease and that its inhibition will be of therapeutic benefit. Other studies focusing on AD or ALS showed an improvement when inhibiting this pathway. Thus, we plan to test this approach in PD pre-clinical models.
To study whether inhibition of the CD40-CD40L neuroinflammation pathway is of potential therapeutic benefit, we will use transgenic mice that lack a key component of the pathway: the CD40 ligand (CD40L). We will induce PD-like changes in these pre-clinical models, and in controls, by treating them with two commonly used neurotoxins: 6-hydroxydopamine, and Paraquat. After that, we will examine whether the dopaminergic neurons are protected in the models lacking CD40L, an observation that would confirm our hypothesis. We will also measure if neuroprotection correlates with less neuroinflammation, which typically means less activation of the resident brain microglia. Such an observation would indicate that, indeed, by blocking neuroinflammation through the inhibition of the CD40-CD40L pathway, one can achieve a therapeutic effect.
Relevance to Diagnosis/Treatment of Parkinsonís Disease:†††††††††††††††††††††
Our study will answer the question if disrupting the CD40-CD40L pathway is of therapeutic benefit in pre-clinical models of PD. This finding could open a new avenue for therapeutic intervention in PD, where current therapeutic options are limited mainly to dopaminergic replacement therapies. Antibodies neutralizing CD40 or CD40L exist and are currently being clinically tested to treat autoimmune diseases and organ rejection after transplantation. They could be tested in PD models in a follow-up to our study.
We will learn whether inhibition of the CD40-CD40L pathway is neuroprotective in pre-clinical PD models. We also believe this neuroprotection will be directly correlated with diminished neuroinflammation. This approach has worked in pre-clinical models of other neurodegenerative diseases. As antibodies targeting the CD40-CD40L pathway do exist, if our investigations are successful, they could pave the way for studies that will ultimately lead to clinical testing of this approach in PD.
INTERIM PROGRESS REPORT
The CD40-CD40L pathway is a chain of events that unfolds inside and outside the cell during an immune response. In this study, we hypothesized that the activation of the CD40-CD40L pathway promotes Parkinson's disease (PD) and that turning off this pathway may help cure the disease. To test this hypothesis, we used pre-clinical models that lack CD40L, the key component of this pathway. We treated pre-clinical models lacking CD40L and normal models with a toxin that damages dopamine-producing cells in the brain. Contrary to our expectations, the lack of CD40L did not protect brain cells of these models from death. Furthermore, we were unable to confirm that models with disabled CD40/CD40L pathway have fewer activated microglia -- immune cells residing in the brain -- in the dopamine-producing region. An undesirable ability to damage surrounding brain cells, microglia activation persisted in models with disabled CD40/CD40L pathway. Although preliminary, our data does not confirm disruption of the CD40/CD40L pathway as therapeutic in PD. However, we still consider CD40 a promising therapeutic target and plan to test this hypothesis in a different pre-clinical model.
Chief Scientific Officer at AxoGlia Therapeutics SA
Location: Luxembourg City,
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