Joint Transnational Call 2023 (JTC2023)
CADASIL-Natural HIStory (CADANHIS)
There is no therapy to prevent the progression of CADASIL, a rare small hereditary vessel disease leading to stroke and to progressive motor and cognitive decline. Many barriers obviously limit the development of therapeutic research. The objectives of the CADANHIS project are to overcome these latter, particularly : 1) to better understand the current practices to manage and treat patients in different European countries, 2) to make a quantum leap in the prediction of individual disease progression with modelling the natural history of the disease, 3) to improve our knowledge of patients’ and families’ complaints and develop a set of patients reported outcomes (PROs), 4) to determine the most relevant imaging or clinical outcomes for future clinical trials at different disease stage, 5) to identify circulating biomarkers associated with white-matter tissue lesions at the earliest stage of the disease; 6) to identify sensitive blood (or CSF) biomarkers related to the accumulation of Notch3-ECD or to alterations of mural cells in microvessels for monitoring the vascular disease progression in the brain and measuring therapeutic effectiveness.
The CADASIL-Natural HIStory (CADANHIS) consortium will assemble: 1) patients, families and their representatives from five European countries, 2) clinicians, psychologists and researchers with a large experience of care and studies in CADASIL, 3) clinical, biological, genetic and imaging data already collected from cohorts making a total of over 1000 patients, 4) unique expertise in biology, transcriptomics, experimental models, clinical investigations, cognitive testing, imaging as well as in methodology and statistics.
The first work-package of the project aims at building a common database for sharing clinical, imaging, genetic and biological resources gathered through years of CADASIL patients’ follow-up in five countries. This will be obtained by harmonizing all the data and will allow defining a CADANHIS minimum data set to ease further inclusion and follow-up.
Then, in the second work-package, we will map the natural history of CADASIL using all collected information and according to the “disease course mapping method” in order to determine the best predictors of its variability according various outcomes at different disease stages.
In parallel, in the third work-package, we will try to evaluate the disease impact on patient’s quality of life, through different ways. We will conduct a large survey of CADASIL patient on their current clinical management and a questionnaire evaluating the patient and family complaints. Finally, we will build a multi-lingual Patient’s reported outcome measurement system in association with patients and families. These tools will allow to develop new outcomes that could really affect patient quality of life.
In the fourth work-package, we will aim at identifying biomarkers of vascular disease progression using CADASIL mouse model and patients samples. To that purpose we will determine whether blood or CSF dosage of Notch3-ECD levels are related to vascular disease progression in a CADASIL mouse model and thereafter in CADASIL patients. We will identify circulating biomarkers possibly related to mural cell alterations using quantitative transcriptomics and proteomics from mouse and human cerebral microvessels. We will also search for circulating biomarkers related to mural cell alterations using transcriptomics from human skin microvessels. The biological role of candidate circulating vascular biomarkers will be finally analyzed in humanized SMCs culture models. In parallel, highly sensitive circulating and imaging markers related to the progression of white-matter tissue lesions will be sought at the earliest stage of the disease. Moreover, alteration of cerebrovascular reactivity (CVR) measured by transcranial Doppler will be assessed as a potential predictor of ischemic manifestations during the course of the disease.
The impact of our project will be multifaceted and major. We will aggregate clinical data from more than 1000 CADASIL patients from five countries and will address the patient perspective in the management of the disease and design of clinical outcomes. The knowledge about disease progression will be enriched by information from patients, families experience from different countries. Prediction will be considerably improved, and new tools will help monitoring disease progression and effectiveness of treatments.
- Chabriat (Coordinator [FRANCE]
- Tezenas Du Montcel [FRANCE]
- Fernández Cadenas [SPAIN]
- Campos [SPAIN]
- Canavero [ITALY]
- Karlström [SWEDEN]
- Tiedt [GERMANY]