Novel Inhibitors of Protein Aggregation as Potential Therapeutics for Parkinson’s Disease

Study Rationale: 
The protein alpha-synuclein can aggregate in brain cells, which leads to brain cell death in Parkinson’s disease (PD). We plan to investigate a novel class of drugs — called protein-protein interaction (PPI) inhibitors — to inhibit the accumulation and aggregation of alpha-synuclein in PD. Our most promising PPI inhibitor reduces the buildup of harmful alpha-synuclein in isolated brain cells. Now, we have modified this inhibitor to allow it to be delivered by intravenous infusion instead of injection into the brain. For the proposed project, we plan to perform a pre-clinical evaluation of this PPI inhibitor in pre-clinical models of Parkinson’s disease.

Hypothesis:
Our PPI inhibitor can be effectively delivered to the brain, where it will reduce the accumulation of harmful alpha-synuclein and thereby prevent brain cell death in pre-clinical models of PD. 

Study Design:
We will first perform pharmacological studies to determine the best ways to deliver the optimal dosage of our PPI inhibitor. Next, we will perform toxicity screening studies to ensure that the selected delivery and dosing strategies are not associated with any adverse effects. We will then evaluate the therapeutic effects of our peptide in two pre-clinical models of PD. Finally, we will initiate a search for small molecules that provide the same function as our PPI inhibitors, as such compounds might be easier to deliver therapeutically. 

Impact on Diagnosis/Treatment of Parkinson’s Disease:
Our project will investigate a completely new class of therapeutics which has been unexplored in Parkinson’s disease until now. Our PPI inhibitors prevent the accumulation of harmful alpha-synuclein aggregates, which is a novel disease-modifying approach for PD. Additionally, we will gather important information about the application of PPI inhibitors in Parkinson’s, which will be useful in future biomedical research.  

Next Steps for Development:
Successful completion of our project will advance our PPI inhibitor for Parkinson’s disease along the drug development pipeline.