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.

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Key information

Conditions

CADASIL Brain Diseases Brain Infarction Brain Ischemia Cardiovascular Diseases Central Nervous System Diseases Cerebral Arterial Diseases Cerebral Infarction Cerebral Small Vessel Diseases Cerebrovascular Disorders Congenital, Hereditary, and Neonatal Diseases and Abnormalities Dementia Dementia, Vascular Genetic Diseases, Inborn Infarction Intracranial Arterial Diseases Ischemia Necrosis Nervous System Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms Stroke Vascular Diseases

Age range

30 year–60 year

Sex eligibility

All sexes

Study type

Observational

Primary location

INSERM

Paris, 75010, France

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

Between 30 and 60 years;
Having a social security scheme or, CMU ;
Diagnosis of CADASIL confirmed by molecular analysis performed previously (missense mutation in the Notch3 gene affecting the number of cysteine in one of the 34 EGFR of NOTCH3 ) ;
No countra-indication for a skin biopsy (ongoing treatment with anti-coagulant, history of bleeding disorder or deficiency of blood clotting factors) ;
Written consent given.

Exclusion criteria

Patients without social security scheme or, CMU ;
Patients aged under 30 or over 60 years at the time of the first visit ;
Pregnant women beyond the 5th month of pregnancy
Patients who are not able to give informed consent ;
Countra-indication to the achievement of the skin biopsy ( ongoing treatment with anti- coagulant, history of bleeding disorder or deficiency of coagulation factors ) .

Treatment and study plan

Skin biopsy

Other

Primary outcomes

Derivation of iPS cells from skin biopsies of patients with CADASIL

Time frame: 30 months

Secondary outcomes

Differentiation of iPS cells to vascular smooth muscle cells, phenotypic and mechanistic analyses

Time frame: 24 mois

Differentiation of iPS cells to vascular smooth muscle cells and phenotypic analysis (12 mois) Mechanistic analyses (12 mois)

Sponsors and collaborators

Lead sponsor

Institut National de la Santé Et de la Recherche Médicale, France

Other Gov

Registry information

Official study title

Obtention d'un modèle Cellulaire de la Maladie CADASIL à Partir de Fibroblastes cutanés de Patients

Important dates

Study start: 2014
Primary completion: 2015
Study completion: 2015
First posted: Jan 9, 2014
Registry last updated: May 16, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

Published trials that share one or more normalized conditions with this study.

Completed