Generation of Powerful Biological Tools for Understanding the Pathophysiology of Chronic Granulomatous Disease. (FIBRO CGD)

September 27, 2017 updated by: University Hospital, Grenoble

Generation of Powerful Biological Tools - Fibroblast or Inducible Pluripotent Bone Marrow Cells - for Understanding the Pathophysiology of Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is a rare genetic disease of innate immune due to the malfunction of phagocytic cells unable to destroy pathogens during infection. The four genes implicated are CYBB, CYBA, NCFA and NCF2 respectively encoding Nox2, p22phox, p47phox and p67phox. Nox2 analogs have recently been discovered in cells other than phagocytes. So the question arises on physiopathological impact of the absence of theses proteins not only in phagocytes but also in other cells types such as fibroblasts or neurons.

The principal objective is thus to study the impact of protein deficits Nox2 and p22phox, in the pathophysiology of neurons from inducible pluripotent bone marrow cells (iPSC).

For this purpose, a collection was built of fibroblasts and keratinocytes from patients with different forms of CGD to get iPSC similar to embryonic marrow cells and differentiable into several cell types (neurons, phagocytes).

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Non randomised pilot descriptive multicentric study. Since recently it has been shown that Nox2p22phox protein is expressed not only in phagocytic cells but also in non-phagocytic cells such as fibroblasts, epithelial cells ,vascular cells, neurons. If pathological consequences of the deficiency Nox2 and p22phox, essential to the production of bactericidal toxic derivatives at the level of phagocytic cells, is well documented, impact of their absence in other types of non-phagocytic cells is not known. A better understanding of the impact of the absence of these proteins in these tissues could improve the management of CGD patients by providing a more specific monitoring of their condition. Similarly the formation of different cell models of all genetic forms of CGD that do not exist at present will be of great use to study the physiopathology of this disease and as tools for future studies.

The study requires the inclusion of minor subjects as CGD is usually diagnosed in early childhood ( <2 years), it is rare (frequency 1/200 000) and the life expectancy is reduced.

To elaborate the cells collection, hair and skin biopsy are necessary. They will be performed under local anesthesia for adults, and during a planned general anesthesia for minors.

Fibroblasts and keratinocytes in culture will be obtained by conventional control methods and the absence of expression of p22phox or Nox2 will be checked.

Measurement of the kinetics of neuronal development and apoptosis iPSC will be performed in a differentiation system 2 dimensions on stromal cells MS5. For that, markers of neuronal differentiation of each step will be measured.

Measurement of Reactive Oxygen Species (ROS) in phagocytes and p22phox deficient Nox2 from differentiation from iPSC (chemiluminescence, flow cytometry) will be performed.

Measurement of the effectiveness of phagocytosis (phagocytic function) in phagocytes deficient p22phox and Nox2 from differentiation from iPSC (flow cytometry) will be performed.

The absence of protein and p22phox Nox2 in phagocytes and p22phox deficient Nox2 from differentiation from the iPSC (western blot, flow cytometry) will be verified.

Kinetic of transformation of fibroblasts derived from CGD patients with deficiency or p22phox Nox2 in myofibroblasts will be measured.

To answer the principal objective of this study the recruitment of 10 patients will be necessary.

Study Type

Interventional

Enrollment (Actual)

3

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
    • Cs10217
      • Grenoble, Cs10217, France, 38043
        • University Hospital, Grenoble Alpes

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

6 months and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • diagnostic of chronic granulomatous disease (CGD) with determined genetic form
  • for minors, patient requiring installation or removal of deep venous general anesthesia.

Exclusion Criteria:

  • patients with acute infections scalable to practice of skin biopsy under local anesthesia
  • patient with impaired hemostasis acquired (drug) or innate.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Chronic Granulomatous Disease
Sample collection were performed from patients with chronic granulomatous disease linked to X or due to Autosomal Recessive (AR) forms AR220, AR470 and AR670.
Other: samples collection : hair and skin biopsy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
to study the impact of protein deficits Nox2 and p22phox, in the physiopathology of neurons from inducible pluripotent bone marrow cells (iPSC)
Time Frame: one year
measurement of the kinetics of neuronal differentiation and identification of subtypes cell formed
one year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To study the impact of protein deficits Nox2 and p22phox on cytochrome b558 synthesis process of phagocytes from inducible pluripotent bone marrow cells ( iPSC ).
Time Frame: 6 months
Evaluation of the synthesis of cytochrome b558 by phagocytes from the transformation of iPSC as a cellular model for studying the impact of the lack of p22phox and Nox2
6 months
To study the impact of protein deficits Nox2 and p22phox , at the physiology of fibroblasts and their transformation into myofibroblasts
Time Frame: two years
Measuring markers of transformation of fibroblasts into myofibroblasts
two years
Constitute cellular models of different types of CGD for future physiopathological studies and therapeutic trials
Time Frame: for years
Get neutrophils and monocytes from the iPSC having the characteristics of human neutrophils of different genetic forms of CGD
for years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Grenoble

Investigators

  • Principal Investigator: Dominique PLANTAZ, University Hospital, Grenoble

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2010

Primary Completion (Actual)

June 1, 2017

Study Completion (Actual)

June 1, 2017

Study Registration Dates

First Submitted

October 4, 2016

First Submitted That Met QC Criteria

October 4, 2016

First Posted (Estimate)

October 6, 2016

Study Record Updates

Last Update Posted (Actual)

September 29, 2017

Last Update Submitted That Met QC Criteria

September 27, 2017

Last Verified

September 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 38RC09.018
  • 2009-A00944-53 (Other Identifier: ID RCB)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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