Assessing the disease severity in CADASIL using patients iPSC-derived models of the neurovascular unit

CADASIL is a hereditary cerebral small vessel disease caused by mutations in the NOTCH3 gene. Small vessel diseases affect the small penetrating arteries and brain capillaries and patients often suffer of migraine, ischaemic stroke, and cognitive decline. Despite its severity, no disease-modifying treatments are available to date. Classical pathogenic mechanisms are associated with cysteine gain or loss in NOTCH3 extracellular domain, but recent studies suggest that mutation site and other polygenic influences may affect disease severity.  In the lab, we have developed a human in vitro model using induced pluripotent stem cells (iPSC) from CADASIL patients to identify new modifying factors which can be targeted therapeutically. The main aim of the project is to establish iPSC models of CADASIL patients with mild and severe phenotype recruited at the Cambridge Stroke clinic and use these models for omics analysis, mechanistic studies, and drugs screening. The project includes a number of techniques: 2D and 3D iPSC-based neurovascular unit models, transcriptomic, proteomic, phenotypic and functional cell assays and high-throughput screening.