Study Rationale: There is a dire need to discover and develop novel therapeutics for Parkinson’s disease (PD), a disorder for which no disease-modifying therapies exist. Targeting the sigma-2 receptor is a promising approach. PD is characterized by an accumulation of abnormal aggregates of alpha-synuclein—and sigma 2 receptors are part of a cellular mechanism for degrading such protein aggregates. Previously, we identified small molecules that modulate sigma 2 receptor activity and that block alpha-synuclein aggregation and toxicity in isolated neurons. In this study, we will evaluate therapeutic benefit of two of these candidate compounds in a pair of different preclinical PD models.
Hypothesis: We hypothesize that the candidate sigma-2 antagonists will be effective in reversing key features of PD in preclinical PD models.
Study Design: Two chemically and functionally distinct sigma-2 modulators will be compared head-to-head in two different preclinical PD models. The efficacy of these modulators will be evaluated by assessing their ability to slow the propagation of alpha-synuclein aggregates, restore dopamine neurotransmission, prevent death of dopamine-producing cells and alleviate motor deficits. In addition, the impact each compound has on gene expression, protein production, and neuronal activation will be measured to pinpoint a precise therapeutic mechanism of action and to support the development of biomarkers that can be used to monitor the drugs’ effects on the target pathway, sigma-2 receptor and disease modification.
Impact on Diagnosis/Treatment of Parkinson’s disease: If successful, a clinical candidate can be advanced to testing in clinical trials to guide the selection of doses that will be disease modifying and beneficial in people with PD.
Next Steps for Development: If candidate CT1812 shows efficacy, we will attempt to secure the necessary partnerships to move to a Phase 2 clinical trial in people with PD. If candidate CT2168 is superior, we will advance this compound to IND-enabling studies to evaluate its pharmacokinetics and toxicology.