Generation of a Cellular Model of CADASIL From Skin Fibroblasts

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

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 Overview

• Status: Unknown
• Conditions: CADASIL
• Intervention / Treatment: Other: Skin biopsy

• Study Type: Observational
• Enrollment (Anticipated): 10

Contacts and Locations

Study Locations

• France
  • Paris, France, 75010
    • Inserm

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 28 years to 58 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

patients with CADASIL managed at the reference centre for rare vascular diseases of the central nervous system and the retina (CERVCO) (Lariboisière Hospital, Paris, France)

Description

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 ) .

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
CADASIL; patients with CADASIL	Other: Skin biopsy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Derivation of iPS cells from skin biopsies of patients with CADASIL	30 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differentiation of iPS cells to vascular smooth muscle cells, phenotypic and mechanistic analyses	Differentiation of iPS cells to vascular smooth muscle cells and phenotypic analysis (12 mois) Mechanistic analyses (12 mois)	24 mois

Collaborators and Investigators

• Sponsor: Institut National de la Santé Et de la Recherche Médicale, France
• Investigators: Principal Investigator: Anne JOUTEL, MD, PhD, Institut National de la Santé Et de la Recherche Médicale, France

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Anticipated): August 1, 2018
• Study Completion (Anticipated): August 1, 2018

Study Registration Dates

• First Submitted: January 3, 2014
• First Submitted That Met QC Criteria: January 7, 2014
• First Posted (Estimate): January 9, 2014

Study Record Updates

• Last Update Posted (Estimate): December 7, 2016
• Last Update Submitted That Met QC Criteria: December 6, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Ischemia; Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Genetic Diseases, Inborn; Brain Ischemia; Dementia; Infarction; Stroke; Brain Infarction; Cerebral Arterial Diseases; Intracranial Arterial Diseases; Cerebral Small Vessel Diseases; Cerebral Infarction; Dementia, Vascular; CADASIL; Dementia, Multi-Infarct
• Other Study ID Numbers: C13-34; 2013-A00994-41 (Registry Identifier: IDRCB)