This project aims to develop a small molecule-based therapeutic targeting transforming growth factor beta (TGFB) signaling for the treatment of Parkinson’s disease (PD). TGFB is a protein that controls cellular functions. Researchers have demonstrated that increasing TGFB signaling blocks neurodegeneration induced by the neurotoxin MPTP and have been developing a small molecule that activates TGFB signaling. In this project these researchers will investigate the efficacy of this TGFB agonist in pre-clinical models of PD.
They will first perform pharmacokinetic/pharmacodynamic relationship studies and determine optimal dosage schemes using TGFB-reporter models. Then the researchers will carry out efficacy studies in a chronic MPTP model to determine if the compound can rescue damage after neurodegeneration has started.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
TGFB has been shown to have multiple associations with PD, as well as with the nigrostriatal system (a major dopamine pathway). However, no direct causal relationship has been established so far between TGFB signaling and the pathogenesis of PD. This project may shed novel insights into the role of TGFB signaling in the pathogenesis of Parkinson’s and validate TGFB signaling as a potential target for a disease-modifying therapy for the disease.
Researchers expect that their small molecule compound will have therapeutic effects in pre-clinical models of PD. As the goal is to develop the compound as a therapeutic for patients with PD, if the compound shows efficacy against parkinsonism in pre-clinical models, they will file an Investigational New Drug (IND) application with the FDA and move to clinical trials in humans.