L6 Evaluation of pridopidine in the transgenic yac128 mouse model of huntington’s disease

Abstract

Pridopidine is currently in clinical development for Huntington’s disease (HD) and investigations to increase the understanding of its therapeutic benefit and mode of action are undergoing. In this study, we aim to investigate the efficacy and mechanism of action of pridopidine using the transgenic YAC128 mouse model of HD. Pridopidine was administered to animals starting at early (1.5 months of age) or late stages of disease (8 months of age). In the early treatment cohort, animals were divided into three groups receiving 0, 10, or 30 mg/kg of pridopidine for a period of 10.5 months. In the late cohort, animals were divided into two groups receiving either 0 mg/kg or an escalating dose of pridopidine (10 mg/kg in week 1, 20 mg/kg in week 2, and 30 mg/kg in weeks 3–8). Pridopidine treated animals were evaluated using a battery of behavioural tests. Our analysis reveals that chronic treatment with pridopidine improves motor coordination and depressive-like phenotypes in the YAC128 HD mice. Currently, neuropathological analysis by immunohistochemistry and structural MRI, and molecular assessments to investigate the mechanism of action of pridopidine are ongoing. At the same time, the observed antidepressant effect of pridopidine after chronic treatment in the YAC128 HD mice prompted us to question whether this effect would also be observed after acute treatment. For this, we are currently breeding a new cohort of mice to further evaluate the effect of acute treatment with pridopidine on anxiety- and depressive-like behavioural phenotypes in HD.