Objective/Rationale:
The therapeutic drug we will repurpose for Parkinson’s disease (PD) is fasudil, a kinase inhibitor with an impressive safety profile in humans. The target of fasudil is highly active under conditions of inflammation and injury, and target inhibition by fasudil enhances axonal growth, regeneration, and promotes neurological recovery following spinal cord injury, making fasudil a promising therapeutic drug for neurological diseases. In addition, fasudil has been shown to be neuroprotective against oxidative stress and suppresses inflammatory responses, both of which have been implicated in the etiology of PD. The objective of this project is to determine whether fasudil has the therapeutic potential to protect and restore degenerating nigrostriatal neurons.
Project Description:
In this proposal, we will validate the therapeutic use of fasudil in pre-clinical models of PD. Specific questions we will be answering include: whether fasudil crosses the intact blood brain barrier, whether fasudil impacts levodopa efficacy or the emergence of levodopa induced dyskinesias, and whether fasudil protects neurons, or even halts ongoing neurodegeneration caused by overexpression of alpha-synuclein.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The repurposing of fasudil for PD would be rapid; fasudil is available in an oral tablet, and shown to have a very favorable safety profile in humans. The existing clinical safety profile makes fasudil an attractive therapeutic for the treatment of PD. Fasudil also has the potential to offer more than Symptoms & Side Effects motor relief to PD patients, and could serve as a safe and effective neuroprotectant in PD patients.
Anticipated Outcome:
Upon successful completion of this project and milestones, fasudil has the potential to be a novel therapeutic in the treatment of PD. Knowing the mechanism of how fasudil rescues alpha-synuclein toxicity will help drive the clinical development for PD. In addition, this work may identify cellular pathways and/or proteins that can be modulated to protect cells from the toxicity of alpha-synuclein.
Final Outcome
The purpose of this project is to determine whether the cardiovascular drug fasudil could be repositioned as a therapeutic for the treatment of Parkinson’s Disease (PD). Drs. MacKeigan and Sortwell have shown, by incorporating fasudil into the chow of preclinical models, that not only do the animals tolerate the drug well, but both high and low doses can reach the brain. In addition, their data supports fasudil increasing dopamine and its metabolites without impacting the magnitude of dyskinesias. Most importantly, fasudil significantly reduced the level of neurodegeneration in these preclinical models and these findings are the first to demonstrate that an orally-administered agent can protect in this particular preclinical model of PD. In summary, the research has demonstrated that fasudil is safe and well-tolerated, reaches the brain and enhances dopamine levels, and finally that fasudil remains a strong clinical candidate as a neuroprotective treatment for PD.
April 2017