Promising Outcomes of Original Grant:
In our past studies, we aimed to identify small molecule inhibitors of proteins called deubiquitinases (DUBs), i.e., chemicals that makes DUBs unable to perform their function in the cell. These proteins have been identified as therapeutic targets for inherited Parkinson's disease (PD) linked to mutations (changes) in the PRKN gene. As a result, we developed inhibitors that can serve as tools for testing whether deactivation of DUB can treat PD in pre-clinical models. When continued, these studies are expected to identify a therapeutic candidate suitable for evaluation in clinical trials.
Objectives for Supplemental Investigation:
Earlier in the course of our studies, we developed assays -- experimental setups -- and used them to evaluate the DUB inhibitor tools. These assays will be used again in the future to optimize the DUB inhibitors. Through this optimization, we aim to identify those suitable for testing in pre-clinical models with Parkinson's features. Ultimately, we aim to evaluate the potential therapeutic benefit of these inhibitors in people with PD. To ensure that the inhibitors are suitable for clinical studies, we will need to confirm that they work as intended and travel to the brain. The additional funding would allow us to identify the signs (also called markers) of the inhibitors successfully accomplishing both in pre-clinical models. These markers would also be useful in measuring the effectiveness of the DUB inhibitor drugs in future clinical studies. To summarize, we will develop optimized DUB drugs and identify markers that will indicate the ability of these drugs to reduce symptoms and/or slow the disease progression.
Importance of This Research for the Development of a New PD Therapy:
In two or three sentences, describe how this work holds potential to forward progress toward a new treatment for Parkinson's. (Approx. 100 words)
Removing toxic proteins or improving impaired processes that take place in Parkinson's can benefit people with the disease. DUB inhibitors can accomplish both in cellular and pre-clinical models; therefore, we anticipate that these inhibitors could potentially alleviate disease symptoms or alter disease progression in people with PD.