Study Rationale: Mitochondrial dysfunction in dopamine-producing neurons is one of the hallmarks of Parkinson’s disease (PD) pathology. Inside mitochondria is a protein called Paraoxonase 2 (PON2), which displays antioxidant and anti-inflammatory properties. This protein has been proposed to play an important role in protection against PD. We have found that our anti-obesity drug, HSG4112, modulates the activity of PON2 and shows a protective effect against PD. However, the exact link between PON2, HSG4112 and PD is yet unknown.
Hypothesis: We hypothesize that HSG4112 can modulate PON2 and provide beneficial effects against PD, and that PON2 will provide a novel target for the treatment of PD.
Study Design: Using a preclinical mouse model of PD, we will identify the optimum dose of HSG4112 that provides the greatest benefit. We will measure the drug concentration in cerebrospinal fluid at that optimum dose, which will help us determine a dosage that will be safe and efficacious in humans. Finally, we will assess the engagement of PON2 by HSG4112 in the brain to confirm that this modulation is responsible for the drug’s beneficial effects.
Impact on Diagnosis/Treatment of Parkinson’s disease: No therapy exists yet that can alter the course of PD progression. Testing PON2 as a relevant target for the treatment of PD will be a significant step towards developing HSG4112 as the first disease progression-altering drug.
Next Steps for Development: If this study is successful, we are confident that HSG4112 will be safe for testing in a phase 2 clinical trial, in which the drug will be administered for 12 weeks to people with PD to evaluate its efficacy in slowing disease progression.