Cerebral small vessel disease (cSVD) is a major contributor to global health burden, yet effective treatments remain scarce. One of the primary obstacles to developing new therapies is the lack of clinically relevant disease models. Using induced pluripotent stem cell (iPSC) technology, we have created in vitro models of the vascular unit—a key structure affected in cSVD. Our approach utilises iPSCs generated from skin biopsies of patients with monogenic forms of cSVD. These iPSCs are differentiated into brain endothelial-like cells and mural cells, co-cultured in a transwell system to replicate the vascular unit. Across these models, we observed a consistent molecular phenotype reflective of cSVD pathology. We further optimised this system into a 96-well format, enabling the screening of potential therapeutic agents. Specifically, we evaluated several matrix metalloproteinase (MMP) inhibitors, identifying compounds that successfully rescued the disease phenotype. This work highlights the potential of iPSC-based models as a robust platform for drug screening in cSVD and provides compelling evidence that MMP inhibition could represent a promising therapeutic strategy.

SPEAKER BIOGRAPHY

I am a Senior Research Associate in the Stroke Research Group, a position I have held since 2017. My primary research focus is on developing novel treatments for vascular dementia and stroke, conditions that represent significant global health and socio-economic challenges. Central to my work is the use of human stem cell-based models derived from patients affected by these diseases. A cornerstone of my research has been the development of innovative “disease-in-a-dish” models for familial forms of cerebral small vessel disease (SVD), a leading cause of vascular dementia. One such familial SVD arises from mutations in the COL4A gene, which encodes collagen IV, a key structural component of the extracellular matrix in blood vessels. Using this model, I successfully replicated the hallmark leaky small blood vessels observed in patients and demonstrated the potential to reverse this vascular dysfunction using matrix metalloproteinase inhibitors in our lab models, paving the way for promising new therapeutic approaches for vascular dementia.