Generation of a Cellular Model of CADASIL From Skin Fibroblasts

Brief Title

Generation of a Cellular Model of CADASIL From Skin Fibroblasts

Official Title

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

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.

Study Type


Primary Outcome

Derivation of iPS cells from skin biopsies of patients with CADASIL

Secondary Outcome

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




Skin biopsy

Study Arms / Comparison Groups

Description:  patients with CADASIL


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

February 2014

Completion Date

August 2018

Primary Completion Date

August 2018

Eligibility Criteria

        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 ) .




30 Years - 60 Years

Accepts Healthy Volunteers



Anne JOUTEL, MD, PhD, , 

Location Countries


Location Countries


Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

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

Study Sponsor

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

Verification Date

December 2016