Generation of a Cellular Model of CADASIL From Skin Fibroblasts

CADASIL Clinical Trial

Official title:

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

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT02032225
• Other study ID #: C13-34
• Secondary ID: 2013-A00994-41
• Status: Enrolling by invitation
• Phase: N/A
• First received: January 3, 2014
• Last updated: December 6, 2016
• Start date: February 2014
• Est. completion date: August 2018

Study information

• Verified date: December 2016
• Source: Institut National de la Santé Et de la Recherche Médicale, France
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Agence Nationale de Sécurité du Médicament et des produits de santé
• Study type: Observational

Clinical Trial 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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 10
• Est. completion date: August 2018
• Est. primary completion date: August 2018
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 30 Years to 60 Years

Eligibility

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 Design

Observational Model: Case-Only, Time Perspective: Prospective

Related Conditions & MeSH terms

• CADASIL
• Dementia, Multi-Infarct

Intervention

Other:
• Skin biopsy

Locations

Country	Name	City	State
France	INSERM	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Institut National de la Santé Et de la Recherche Médicale, France

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Derivation of iPS cells from skin biopsies of patients with CADASIL		30 months	No
Secondary	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	No