Attenuation of Neuroinflammation by Brain-targeted Liposomal Methylprednisolone (2B3-201) in Two Pre-clinical Models of Parkinson's Disease

Objective/Rationale:
Based on increasing evidence of a chronic, self-sustaining environment of inflammation in the brain – or neuroinflammation – in Parkinson’s disease (PD), the objective of the project is to study if brain-targeted, long-circulating liposomal methylprednisolone (2B3-201) could offer a suitable treatment possibility for PD patients. In specific, the hypothesis will be tested if attenuation of neuroinflammation by 2B3-201 results in significant disease-modifying effects on neurodegeneration and behavior in pre-clinical models of induced and transgenic PD.

Project Description:
Current reviews support two phenomena of disease progression: dopaminergic cell loss and Lewy body accumulation. Two different PD pre-clinical models have been identified to cover both aspects: an acute MPTP-induced model, and a long-term double transgenic model of alpha-synuclein and synphilin-1. The acute model induces a decrease in dopaminergic cells in the striatum and substantia nigra within one week. Treatment with 2B3-201 will be started 24 hours after MPTP; dopaminergic cell loss and neuroinflammation will be studied. The long-term model induces dopaminergic cell degeneration and behavioral changes associated with both aspects of cell loss and Lewy bodies. Changes can be detected with automated longitudinal behavioral testing from age 20 to 48 weeks. Treatment with 2B3-201 will be initiated at 20 weeks, with several treatment regimens.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Neuroinflammation is hypothesized to require a broad therapeutic approach, confirming the lack of treatment benefit of specific inflammatory mediator targeting. Glucocorticoids act on pro- and anti-inflammatory mediators, microglial activation and the blood-brain barrier. Dexamethasone has already shown benefit on dopaminergic cell loss, but it requires frequent, high-dose administration, making it unfavorable for PD. Reviews point toward brain-targeted, sustained delivery of such anti-inflammatory compounds for clinical purposes, significantly impacting the way PD is currently treated.

Anticipated Outcome:
The two-legged project design avoids many pitfalls of PD development. The acute model gives quick feedback on optimal dose response and frequency of administration. The second model gives an excellent behavioral and safety outcome, providing a more relevant Proof-of-Concept for clinical benefit, especially for neuroprotective strategies that will slow or stop disease progression. Significant disease-modifying effects in both pre-clinical models will justify further development of 2B3-201 for Parkinson’s disease.