Study Rationale:
The Parkin protein (encoded by the PARK2 gene that is linked to Parkinson's), has been shown to exert potent neuroprotective effects that could potentially be used to treat Parkinson's disease (PD). Cellivery has developed a recombinant cell-permeable Parkin protein (iCP-Parkin) using macromolecule intracellular transduction technology (MITT), a technique that can deliver active Parkin directly into cells and tissues; this delivery mechanism may help recover biochemical and behavioral defects in pre-clinical PD models. This project aims to clarify the protective action of iCP-Parkin and to optimize protocols for its therapeutic administration in clinical testing.
Hypothesis:
Since iCP-Parkin utilizes the same mechanisms as Parkin, iCP-Parkin is expected to function as the Parkin naturally present in cells. Therefore, we hypothesize that iCP-Parkin will cause mitophagy (controlled break down of mitochrondria, the powerhouse of the cell) and increase accumulation of alpha-synuclein, the sticky protein that clumps in those with PD, and/or its clearance.
Study Design:
To better understand interactions between iCP-Parkin, PINK1 (expressed by the PINK1 gene, also associated with PD) and mitochondria, Parkin and mitophagy will be monitored in toxin (CCCP and MPP+)-treated cells using imaging methods to evaluate the effect of iCP-Parkin treatment ubiquitination (protein modulation). iCP-Parkin-mediated clearance of alpha-synuclein will be analyzed by monitoring alpha-synuclein levels and its aggregates and ubiquitination of alpha-synuclein-overexpressed cells and brain tissues. In the cellular model, inhibitors that block the break down of alpha-synuclein will determine which processes are influenced by iCP-Parkin. Dosing will be optimized based on biomarker readouts, effects on behavior, dosage frequency and routes of administration in pre-clinical models.
Impact on Diagnosis/Treatment of Parkinson's disease:
In addition to identifying a clear mode of action of cell-permeable recombinant Parkin protein, the results from this study may demonstrate that iCP-Parkin alters the course of disease progression, as well as affects motor symptoms, by replenishing Parkin in damaged dopaminergic cells.
Next Steps for Development:
We plan to carry out pre-clinical studies and establish protocols for clinical testing. We hope to then file an Investigational New Drug application with the US Food and Drug Administration. Outcomes from this series of studies will provide the foundation for future studies of iCP-Parkin as a protein-based therapeutic for PD. Our ultimate goal is to develop iCP-Parkin as a first-in-class disease-modifying therapeutic for Parkinson's.