Clinical trial NCT02032225: 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
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: CADASIL
Lead sponsor: Institut National de la Santé Et de la Recherche Médicale, France
Sponsor class: OTHER_GOV
First posted: 2014-01-09
Enrollment: 8
Sex: ALL
Minimum age (years): 30
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
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)

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.


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 ) .

Primary outcomes:
measure: Derivation of iPS cells from skin biopsies of patients with CADASIL
timeFrame: 30 months
Secondary outcomes:
measure: Differentiation of iPS cells to vascular smooth muscle cells, phenotypic and mechanistic analyses
timeFrame: 24 mois
Other outcomes:
Locations:
city: Paris
country: France
facility: INSERM
Study officials:
affiliation: Institut National de la Santé Et de la Recherche Médicale, France
name: Anne JOUTEL, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: