Study Rationale: Proteasomes are cylinder-like structures inside cells that breakdown unnecessary or damaged proteins. When proteasomes do not work properly, the unwanted proteins may accumulate and harm the cell. This is a problem in Parkinson’s disease where proteasomes do not function well causing the protein alpha-synuclein to accumulate and forms clumps inside the cell. These clumps in turn make the proteasome’s job even harder which creates a vicious cycle that leads to the death of brain cells. Booster’s approach targets this problem by using an innovative approach to find a small molecule to help activate proteasomes, offering hope for a new treatment for Parkinson’s.
Hypothesis: A safe compound that can enter the brain and activate the proteasome might reduce the amount of harmful alpha-synuclein, protect brain cells and slow or even stop the progression of Parkinson's disease.
Study Design: The main goal of this proposal is to find and a novel small molecule that activates the proteasomes, ready to be tested in toxicology studies to support future clinical trials. First, we will identify specific biomarkers of proteasome activity in body fluids. We will explore the in vivo effect of proteasome activators on known biomarkers of Parkinson’s disease, like misfolded proteins and brain cell damage; we will also look at biomarkers of brain inflammation and oxidative stress. Next, we will design and synthesize improved proteasome activators that can be developed for clinical use; finally, we will test the best drug candidate in a relevant in vivo animal model in preparation of studies to support clinical trials.
Impact on Diagnosis/Treatment of Parkinson’s disease: There are currently no drugs that can activate the proteasome. Thanks to new technology developed by Booster, we can create compounds with drug-like properties that help improve the function of the proteasome. This is a new approach in Parkinson’s Disease treatment and could lead to a therapy that changes the course of the disease.
Next Steps for Development: Upon successful completion of this project, we will have a promising drug candidate tested in in vivo pre-clinical models, open the way to the studies that will lead human clinical trials. Thorough safety and toxicology studies will be conducted thereafter, to make sure the compound is safe and ready for human clinical trials.