Goal:
- In a 2-year transatlantic natural history study of each ARSACS and SPG7 we will longitudinally validate clinician- and patient-reported, digital and molecular outcomes.
Description:
Spastic ataxias (SPAX) present an expanding group of >100 rare neurodegenerative diseases with joined damage of cerebellum and corticospinal tract (CST). While rapid genetic stratification facilitates current development of molecular therapies, effective trial-planning for SPAX is hampered by a lack of valid outcome measures and natural history studies. Building on the ARCA GLOBAL network as well as other pre-existing networks, PROSPAX will establish a paradigmatic IRDiRC-guided integrated trial-ready model of disease progression and mechanistic evolution in SPAX, focusing paradigmatically on ARSACS and SPG7. This endeavor will allow to track and understand selective as well as overlapping dysfunction of the cerebellum and CST. In a 2-year transatlantic natural history study of each ARSACS and SPG7 we will longitudinally validate clinician- and patient-reported, digital and molecular outcomes. In addition, PROSPAX will improve on existing and develop new outcome parameters that show superior sensitivity to change. These include a novel clinical SPAX composite score, a smartphone mHealth toolbox combining remote assessment of daily living by wearable sensors with app-based patient-entered outcomes (SPAX.app), and multimodal MRI radiomics with an innovative machine learning approach for multisite MRI analysis, including in particular the infratentorial space. Longitudinal validation of targeted fluid biomarker candidates will be complemented by single-cell multi-omic studies in ARSACS and SPG7 mouse which will allow to identify shared pathways and vulnerabilities between cerebellar and corticospinal neurons and will unravel new molecular biomarkers. By focusing on these two most prevalent recessive SPAX (SPG7, ARSACS), PROSPAX will create a paradigmatic trial-readiness pathway for charting disease progression and multimodal outcome measures that will be applicable to many of the >100 SPAX diseases as well as other ARCA GLOBAL diseases alike.
| Cohorts used | SPG7, ARSACS |
| Funding available? | Partly available, further funding to be sought |
| Trial readiness category | 2: setting the stage for trial readiness (general cohorts, outcome measures or treatment approach identification) |
Contact persons:
Rebecca Schüle
University of Tübingen, Tübingen, Germany
Further project partners:
Matthis Synofzik
University of Tübingen, Tübingen, Germany