Study Rationale: We are working on a small, drug-like compound that has potential therapeutic application in Parkinson's disease. This drug-like compound specifically inhibits a protein in the cell named USP14. As a result of this inhibition, the central power generator of the cell (the mitochondrion) is renewed: old, poorly functioning power generators are replaced with new ones. In our proposal we test whether our compound, by acting in this way, can improve the health of mice that have been engineered to replicate Parkinson's disease.
Hypothesis: We hypothesize that inhibition of the enzyme USP14 can be therapeutic for Parkinson's disease.
Study Design: Our USP14 inhibitors are injected into pre-clinical models that have a condition essentially replicating Parkinson's disease. We then track these pre-clinical models to see if their condition improves. We monitor the health of these animals at multiple levels, using for example microscopy, biochemistry, and behavioral analysis. In parallel, we will be using neurons of human origin (iNeurons) to address the molecular mechanism underlying the protective effect of USP14 inhibition and the physiological relevance in human neuronal cells.
Impact on Diagnosis/Treatment of Parkinson’s disease: The USP14 inhibitor has rare properties that suggest suitability as a treatment for Parkinson's disease. The experiments we are doing in pre-clinical models for this project put this idea directly to the test. Perhaps it will pass the test; in this case it will be advanced for more testing, particularly in humans.
Next Steps for Development: If we observe clear amelioration of Parkinson's symptoms in the pre-clinical models, with only modest side-effects, we would hope to see the compound advanced to studies in humans. At that point our role would be in large part to advocate for clinical studies in humans and to technically advise on their design, and ultimately the decision to go forward at that point will fall to our colleagues in the private sector.