Helena Karlström

CADASIL is the most common monogenic form of cerebral small vessel disease (SVD), a group of diseases affecting more than 5.000 individuals per year in Sweden. CADASIL is caused by mutations in the NOTCH3 gene and CADASIL patients experience arteriopathy and ischemic infarcts, ultimately leading to cognitive impairment and premature death. There are currently no therapies for CADASIL, and we will therefore explore two novel therapy strategies in a CADASIL mouse model: immunization and neuroinflammation/STING blockade. To monitor disease progression in CADASIL patients, better biomarkers are warranted. We will identify potential biomarkers from a large-scale transcriptomic dataset from a CADASIL mouse model, evaluate candidate biomarkers in human and mouse histological material and assess their efficacy in blood samples from CADASIL patients, with a particular focus on neuroinflammation. Finally,  non-CADASIL disease-causing NOTCH3 mutations are emerging, and we will search for such mutations in a small cohort of “atypical” SVD and migraine patients and establish how non-CADASIL NOTCH3 mutations affect Notch signalling. Information about non-CADASIL NOTCH3 mutations is important for future therapy considerations. In sum, through a multipronged approach spanning from preclinical transcriptomic and mouse model analysis to biomarker analysis in CADASIL patients, we expect to make progress beyond the state-of-the-art in CADASIL therapy and monitoring of disease progress.

There is no therapy to prevent the progression of CADASI and current therapeutic research is limited by many barriers.The CADASIL-Natural HIStory project aims at overcoming these limitations 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’ concerns 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, and

6) to identify sensitive blood/ CSF biomarkers related to the accumulation of Notch3-extracelluar domain or to alterations of mural cells in microvessels for monitoring the vascular disease progression in the brain and measuring therapeutic efficacy. Our consortiums aims at meeting these different objectives by assembling: 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, imaging, genetic, and biological data already collected from cohorts totaling over 1000 patients, and 4) unique expertise in clinical neurology, imaging, biology, as well as in methodology.