TREAT-HD: Delivering therapies to prevent neurodegeneration in Huntington’s disease

Our overarching hypothesis is that mechanistic insights from preclinical models of Huntington’s disease (HD) and their genetic treatment are valid for early human pathogenesis and can therefore be realised as the foundation for transformative, preventive, clinical trials. A major obstacle to treatment is that degenerative conditions are usually diagnosed once compensatory mechanisms have been exhausted and irrecoverable cell death has occurred. TREAT-HD shifts the focus to mechanisms underlying earlier and asymptomatic stages of pathogenesis as a better time to initiate treatment. We test our hypothesis through three inter-linked aims (Figure 1) that establish the earliest consequences of mutant huntingtin protein (mHTT) in cells, mice and humans with the aim of developing novel therapeutics to delay or prevent symptom onset. Aims: 1. Determine molecular mechanisms associated with somatic CAG-repeat expansion as targets for novel therapeutics by examining agents targeting DNA repair pathways in cellular and mouse models of HD 2. Determine early systems-level pathology and impact on symptomatology in young adult HD mutation carriers to test the hypothesis that neurodevelopmental effects on brain structure occur before progressive neurodegeneration 3. Integrate molecular and systems-level insights for therapeutic benefit by identifying and validating target engagement and efficacy markers for future clinical trials