Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy (CADASIL) is an archetypal small vessel disease of the brain caused by dominant mutations in the NOTCH3 receptor. Cardinal vascular lesions include deposition of granular osmiophilic material (GOM) within the basal lamina of smooth muscle cells, progressive smooth muscle cell loss, and fibrosis of the media. Pathogenic mutations alter the number of cysteine residues in the extracellular domain of NOTCH3 (Notch3 ECD), leading to its abnormal accumulation in the GOM deposits. Vascular smooth muscle cell has been identified as the primary target cell in this disease. Pathophysiological processes leading from NOTCH3 mutations to smooth muscle cell loss remain poorly understood. The investigators propose to study these mechanisms by reprogramming skin cells to become stem cells and then differentiating them to vascular smooth muscle cells. The hypothesis of this study is that the differentiated smooth muscle cells will display the characteristic features of CADASIL, ie, Notch3 ECD accumulation and GOM deposits.
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Derivation of iPS cells from skin biopsies of patients with CADASIL
Timeframe: 30 months