What is PROSPAX?
“PROSPAX - an integrated multimodal progression chart in spastic ataxias” is a 3 year international collaborative research project (2020-2023) funded by the European Joint Programme on Rare Diseases (EJP RD). This project unites PIs from all major European ataxia and spastic paraplegia networks: PREPARE, SPATAX, TreatHSP, Alliance for Treatment in HSP and PLS, ERN-RND and SOLVE-RD as well as top PIs from North America and three ataxia and HSP patient organizations to overcome the limitations of current spastic ataxia research.
Spastic ataxias (SPAX) present an expanding group of rare neurodegenerative diseases (prevalence 10-15/100.000) with joined damage of cerebellum and corticospinal tract (CST). They often manifest early in life, with devastating chronically progressive consequences on daily life and treatment options are limited to symptom relief.
By example of the two most common recessive SPAX (SPG7 & ARSACS) PROSPAX aims to 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 alike.
The project is devided into six workpackages:
WP 1 - Multicentric Porspective Natural History Study (NHS)
Chart disease progression in SPG7 and ARSACS by a multisite prospective natural history study across IRDiRC-guided outcome parameter modalities and disease stages.
WP 2 - mHealth Toolbox for Patient-Centered Digital Biomarkers (Spax.app)
Establish and validate a multimodal sensor-based mHealth toolbox for remote home assessment of patient-centered digital biomarkers associated with SPAX disease progression.
WP 3 - Multimodal MRI for Microstructural Brain Biomarkers
Map the brain microstructures underlying SPG7 and ARSACS disease progression, and to identify brain imaging outcome parameters for SPAX trials by automated MRI volumetry.
WP 4 - Cross-Species Multi-Omic Biomarkers and Pathways
Identify and validate molecular biomarkers of disease progression and unravel novel pathways underlying cortical motoneuron and Purkinje cell degeneration in a mouse/human cross-species approach.
WP 5 - Accelerated Diagnosis in SPAX Patients
Accelerate genomic diagnosis in unsolved SPAX patients by identification of novel SPAX genes, functional variant interpretation, and comprehensive genotype-phenotyping.
WP 6 - Trial statistics, integrated model and data management
Establish an integrated model of progression and mechanistic evolution of SPAX disease, including modelling of the relative sequence of change, and to establish a sustainable resource of multimodal SPAX data for future clinical trials.
WP PAO - Systematic identification of patient relevant concepts of interest
Workpackage lead by patient organizations as active equitable research partners. Lead scientific identification of patient relevant concenpts of interest, development of novel patient-centered outcome measures (PCOMs), inform the consortium’s research as patient-partners according to a standardized patient-partner approach, engage patients and the general public.
The main ambitions of PROSPAX are to establish:
- A paradigmatic International Rare Diseases Research Consortium (IRDiRC)-guided integrated trial-ready model of disease progression and mechanistic evolution in SPAX, which will allow to track and understand selective as well as overlapping dysfunction of the cerebellum and CST.
- A 2- year transatlantic natural history study that will longitudinally validate clinician- and patient-reported, digital and molecular outcomes to understand the temporal dynamics of outcome parameter changes over the course of the disease
- Improve 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 multiomic studies in mouse which will allow to identify shared pathways and vulnerabilities between cerebellar and corticospinal neurons and will unravel new molecular biomarkers.
- Allow diagnosis of unsolved spastic ataxia patients by identification of novel genes