To enable polyQ targeting therapies and better predict onset and progression of disease of the different patient groups (early-onset, adult-onset and carriers of intermediate repeats), we will start by creating isogenic human-derived cells with different CAG repeat lengths for 3 different polyQ diseases (WP1) and setup of robust platforms to characterize the landscape of phenotypic consequences whilst differentiating them into specific lineages (2D) or neuronal bodies (3D). In parallel, we will generate these landscapes for iPSC-models derived from cells from actual patients with known ages at onset to find landscape-derived parameters that might predict disease onset of and in relation to the different patient groups (aggregated and generated in WP2), either alone or combined with clinical, imaging and fluid biomarkers (WP3). These landscapes will also be used to evaluate or validate newly-developed therapeutic strategies (WP4). While this will answer questions from clinicians and patient communities, it will also generate new ones, which is why we will study the ethical implications of such improved diagnostics (WP6):