About This Project

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a rare genetic disease with no current cure, profoundly impacting those affected. Symptoms of CADASIL often start in early adulthood and progresses to recurrent strokes, cognitive difficulties, and ultimately, vascular dementia. In my laboratory, we have developed a groundbreaking in vitro model, ‘CADASIL in a dish’, which allows us to study the disease and explore potential treatments.

Ask the Scientists

What is the context of this research?

CADASIL is a rare genetic disorder caused by mutations in the NOTCH3 gene. It typically leads to migraines, recurrent strokes, cognitive decline, and psychiatric symptoms, profoundly affecting patients and their families Alzheimer’s Society. Currently, there is no cure.

At Addenbrooke’s Hospital, University of Cambridge, our "CADASIL in a Dish" project is pioneering a new approach to treatment. We use skin biopsy cells from patients to generate induced pluripotent stem cells (iPSCs), which we then develop into lab-grown small blood vessels that replicate the disease. This innovative model allows us to study the underlying disease mechanisms and test potential therapies in a controlled, human-relevant system with the goal of identifying effective treatments and improving outcomes for those living with CADASIL (Stem Cell Reports, 2023).

What is the significance of this project?

CADASIL is a rare genetic condition affecting 2–5 in 100,000 people. In the UK, a few hundred individuals live with the disease . It affects men and women equally across all racial and ethnic groups and currently has no cure. This project offers a vital opportunity to identify therapies that could improve patient outcomes.

Our “CADASIL in a dish” model has broader significance beyond this condition. Vascular dysfunction, central to CADASIL, is increasingly recognised as a contributor to other neurodegenerative diseases such as sporadic small vessel disease (the most common form of vascular dementia), mixed dementia, Alzheimer’s, Frontotemporal Dementia, and ALS. By using patient-derived cells to model disease and test treatments, we advance personalised medicine and uncover shared mechanisms that could lead to therapies benefiting a broader population

What are the goals of the project?

This project aims to develop a patient-specific in vitro model of CADASIL using iPSCs to study disease and test therapies. Blood vessels are created by differentiating patient-derived iPSCs into endothelial and mural cells, co-cultured in a hydrogel chip that supports vasculogenesis. We will assess hallmark CADASIL features, such as granular osmiophilic material (GOM), which accumulates around blood vessels due to mutant NOTCH3, using immunohistochemistry. We will evaluate treatment response through GOM reduction, improved blood-brain barrier permeability (via FITC-dextran) and mural cell survival and functional markers by gene expression, as these cells regulate vessel stability and integrity. We will test a focused panel of 11 matrix metalloproteinase (Matrix metalloproteinase) inhibitors, as MMPs are implicated in stroke and cognitive decline. Controls include healthy and isogenic CRISPR-corrected iPSC lines. Samples are fully anonymised.