Generation of a Cellular Model of CADASIL From Skin Fibroblasts
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.
|Study Design:||Observational Model: Case-Only
Time Perspective: Prospective
|Official Title:||Obtention d'un modèle Cellulaire de la Maladie CADASIL à Partir de Fibroblastes cutanés de Patients|
- Derivation of iPS cells from skin biopsies of patients with CADASIL [ Time Frame: 30 months ] [ Designated as safety issue: No ]
- Differentiation of iPS cells to vascular smooth muscle cells, phenotypic and mechanistic analyses [ Time Frame: 24 mois ] [ Designated as safety issue: No ]Differentiation of iPS cells to vascular smooth muscle cells and phenotypic analysis (12 mois) Mechanistic analyses (12 mois)
Biospecimen Retention: Samples Without DNA
Skin biopsies will be collected to derive fibroblasts. These will be retained and reprogrammed to iPS cells (also to be retained). iPS cells will be differentiated in vascular smooth muscle cells.
|Study Start Date:||February 2014|
|Estimated Study Completion Date:||August 2018|
|Estimated Primary Completion Date:||August 2016 (Final data collection date for primary outcome measure)|
|Paris, France, 75010|
|Principal Investigator:||Anne JOUTEL, MD, PhD||Institut National de la Santé Et de la Recherche Médicale, France|