Generation of a Cellular Model of CADASIL From Skin Fibroblasts

NCT02032225 | Completed

• 2 other identifiers: C13-342013-A00994-41
• Study Type: observational
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

CADASIL

Outcome Measures

Primary Outcomes (1)

• Derivation of iPS cells from skin biopsies of patients with CADASIL

  30 months

Secondary Outcomes (1)

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

  24 mois

Study Arms (1)

CADASIL

patients with CADASIL

Other: Skin biopsy

Interventions

Skin biopsy OTHER

CADASIL

Eligibility Criteria

• Age: 30 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)
• 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)

You may qualify if:

• 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.

You may not qualify if:

• 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 ) .

Sponsors & Collaborators

• Institut National de la Santé Et de la Recherche Médicale, France: lead

Study Sites (1)

INSERM

Paris, Paris, 75010, France

Location

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.

MeSH Terms

Conditions

CADASIL

Condition Hierarchy (Ancestors)

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

Study Officials

• Anne JOUTEL, MD, PhD

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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 3, 2014
• First Posted: January 9, 2014
• Study Start: February 1, 2014
• Primary Completion: February 11, 2015
• Study Completion: February 11, 2015
• Last Updated: May 16, 2025

Record last verified: 2016-12

Locations

FR (1)