Study Rationale: The formation of tau aggregates is caused by excessive modification and abnormal folding of the tau protein in the brain, which leads to cellular dysfunction and neurodegeneration. Preclinical and clinical studies have shown that inhibiting tau aggregation reduces neurotoxicity and has the potential to prevent the spread of Parkinson’s disease (PD) pathology.
Hypothesis: We hypothesize that targeting tau during the early stages of aggregation will prevent propagation of abnormal tau plaques and potentially alleviate the symptoms of PD.
Study Design: This project will evaluate two compounds, PSY-055 and PSY-106, for their ability to inhibit tau accumulation in cellular models of aggregation and toxicity, including those with the alpha-synuclein A53T and LRRK2 G2019S mutations. We will characterize the compounds’ metabolism and pharmacokinetic properties and then select one for biochemical optimization for further preclinical studies. Next, we will generate proof-of-principle data on the most promising of the two lead compounds in preclinical tau models of PD. Finally, we will optimize our lead compound’s pharmacokinetic profile to produce a candidate drug suitable for studies leading to an IND application.
Impact on Diagnosis/Treatment of Parkinson’s disease: Targeting tau aggregates at the earliest stage of their propagation has the potential to alter the course of PD and significantly impact individuals who receive an early diagnosis.
Next Steps for Development: If this project is successful, we will advance the program into IND-enabling studies as we drive towards entering Phase I clinical trials. The program also has vast potential for the development of treatments for other disorders involving tau aggregation, including Alzheimer’s Disease and frontotemporal dementia.