PBT2 Reduces Toxicity in a C. elegans Model of polyQ Aggregation and Extends Lifespan, Reduces Striatal Atrophy and Improves Motor Performance in the R6/2 Mouse Model of Huntington's Disease

Background: There is evidence that interaction with biologically important metals, particularly copper and iron, contributes to the pathological aggregation and toxicity of the mutant huntingtin protein in HD. PBT2 is a novel 8- hydroxyquinoline drug in clinical trials for AD and HD which restores metal homeostasis and has demonstrated neuroprotective and cognitive benefits in animal models of AD and in a Phase IIa clinical trial in AD patients. Objectives: We assessed efficacy of PBT2 to improve function in nematode and mouse models of HD. Methods: We assessed the effects of PBT2 on motility in a strain of C. elegans engineered to overexpress an extended polyglutamine tract. We then assessed the effects of daily oral administration of PBT2 on the R6/2 mouse a vertebrate model of HD. Behavioural measures (Rotarod performance, clasping latency and duration) and measures of overall health (body weight, lifespan) were assessed throughout the study. At conclusion brains were evaluated for weight and lateral ventricle area. Results: PBT2 significantly decreased paralysis caused by overexpression of an extended polyglutamine tract in a C. elegans. R6/2 mice treated with PBT2 showed significantly better performance in the Rotarod task and significantly decreased duration of clasping than control animals. Mean body weight and brain weight in the PBT2 treatment group were significantly higher than the control cohort and median lifespan was prolonged by 26%. Mean lateral ventricle area in the PBT2- treated group was 46% smaller than in the control group. Conclusions: Treatment with PBT2 may be beneficial as a disease modifying therapy for HD.