Chronic Granulomatous DiseaseFIBRO CGDNCT02926963
Generation of Powerful Biological Tools for Understanding the Pathophysiology of Chronic Granulomatous Disease.
A study testing samples collection : hair and skin biopsy in people with Chronic Granulomatous Disease, run by University Hospital, Grenoble at 1 site in France.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 6 months and older
- Conditions the study is for
- Chronic Granulomatous Disease
- What is being tested?
- samples collection : hair and skin biopsy
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 3 participants
- Where
- 1 siteFrance
- Study dates
- Oct 2010to Jun 2017
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 months and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- diagnostic of chronic granulomatous disease (CGD) with determined genetic form
- for minors, patient requiring installation or removal of deep venous general anesthesia.
Who cannot join
- patients with acute infections scalable to practice of skin biopsy under local anesthesia
- patient with impaired hemostasis acquired (drug) or innate.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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).
Read the 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.
- Conditions
- Chronic Granulomatous Disease
- Being tested
- samples collection : hair and skin biopsy
- Keywords
- Chronic Granulomatous Disease, Nox2, p22phox, iPS cells
- Medical subject headings
- Granulomatous Disease, Chronic, Granulomatous Disease, Chronic, Autosomal Recessive, Cytochrome B-Negative
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
samples collection : hair and skin biopsyOther
| Study group | Role | What they receive |
|---|---|---|
| Chronic Granulomatous Disease | Experimental | Sample collection were performed from patients with chronic granulomatous disease linked to X or due to Autosomal Recessive (AR) forms AR220, AR470 and AR670. Receives: Other: samples collection : hair and skin biopsy |
What is being measured
The primary outcome is the main question the study is designed to answer.
to study the impact of protein deficits Nox2 and p22phox, in the physiopathology of neurons from inducible pluripotent bone marrow cells (iPSC)
measurement of the kinetics of neuronal differentiation and identification of subtypes cell formed
Measured: one year
Secondary outcomes (3)
To study the impact of protein deficits Nox2 and p22phox on cytochrome b558 synthesis process of phagocytes from inducible pluripotent bone marrow cells ( iPSC ).
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
Measured: 6 months
To study the impact of protein deficits Nox2 and p22phox , at the physiology of fibroblasts and their transformation into myofibroblasts
Measuring markers of transformation of fibroblasts into myofibroblasts
Measured: two years
Constitute cellular models of different types of CGD for future physiopathological studies and therapeutic trials
Get neutrophils and monocytes from the iPSC having the characteristics of human neutrophils of different genetic forms of CGD
Measured: for years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Oct 2016 (estimated)
- Study startOct 2010
- Primary completionJun 2017
- Study completionJun 2017
Why it stopped: insufficient recruitment
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Chronic Granulomatous DiseaseStudies of the same condition, open and under way.
- More trials run by University Hospital, GrenobleThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 3 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital, Grenoble
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Dominique PLANTAZ, Principal investigator, University Hospital, Grenoble
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02926963
- Sponsor's protocol ID
- 38RC09.018
- Other IDs
- 2009-A00944-53
- Acronym
- FIBRO CGD
- Status last verified
- Sep 2017
- First submitted
- 4 Oct 2016
- Last updated
- 29 Sep 2017
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
O'Neill S, Brault J, Stasia MJ, Knaus UG. Genetic disorders coupled to ROS deficiency. Redox Biol. 2015 Dec;6:135-156. doi: 10.1016/j.redox.2015.07.009. Epub 2015 Jul 17.
PubMed 26210446Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 2007 Jan;87(1):245-313. doi: 10.1152/physrev.00044.2005.
PubMed 17237347Nakano Y, Longo-Guess CM, Bergstrom DE, Nauseef WM, Jones SM, Banfi B. Mutation of the Cyba gene encoding p22phox causes vestibular and immune defects in mice. J Clin Invest. 2008 Mar;118(3):1176-85. doi: 10.1172/JCI33835.
PubMed 18292807Schiavone S, Sorce S, Dubois-Dauphin M, Jaquet V, Colaianna M, Zotti M, Cuomo V, Trabace L, Krause KH. Involvement of NOX2 in the development of behavioral and pathologic alterations in isolated rats. Biol Psychiatry. 2009 Aug 15;66(4):384-92. doi: 10.1016/j.biopsych.2009.04.033. Epub 2009 Jun 26.
PubMed 19559404Brault J, Goutagny E, Telugu N, Shao K, Baquie M, Satre V, Coutton C, Grunwald D, Brion JP, Barlogis V, Stephan JL, Plantaz D, Hescheler J, Krause KH, Saric T, Stasia MJ. Optimized Generation of Functional Neutrophils and Macrophages from Patient-Specific Induced Pluripotent Stem Cells: Ex Vivo Models of X(0)-Linked, AR22(0)- and AR47(0)- Chronic Granulomatous Diseases. Biores Open Access. 2014 Dec 1;3(6):311-26. doi: 10.1089/biores.2014.0045.
PubMed 25469316
Study at a glance
From the registry record, last updated by the sponsor on 29 Sep 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Generation of Powerful Biological Tools - Fibroblast or Inducible Pluripotent Bone Marrow Cells - for Understanding the Pathophysiology of Chronic Granulomatous Disease.
- ClinicalTrials.gov ID
- NCT02926963
- Acronym / sponsor ID
- FIBRO CGD / 38RC09.018
- Conditions
- Chronic Granulomatous Disease
- Keywords
- Chronic Granulomatous Disease, Nox2, p22phox, iPS cells
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: insufficient recruitment
- Enrolment
- 3 participants (actual)
- Lead sponsor
- University Hospital, GrenobleUniversity, hospital or other
- Study start
- Oct 2010
- Primary completion
- Jun 2017 (actual)
- Study completion
- Jun 2017 (actual)
- First posted
- 6 Oct 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
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 design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Chronic Granulomatous Disease | Experimental | Other: samples collection : hair and skin biopsySample collection were performed from patients with chronic granulomatous disease linked to X or due to Autosomal Recessive (AR) forms AR220, AR470 and AR670. |
Who may qualify
- Ages
- 6 months and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (2 listed)
- diagnostic of chronic granulomatous disease (CGD) with determined genetic form
- for minors, patient requiring installation or removal of deep venous general anesthesia.
Key exclusion criteria (2 listed)
- patients with acute infections scalable to practice of skin biopsy under local anesthesia
- patient with impaired hemostasis acquired (drug) or innate.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| samples collection : hair and skin biopsy | Other | Chronic Granulomatous Disease |
Primary outcome
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
3 secondary outcomes
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
To study the impact of protein deficits Nox2 and p22phox , at the physiology of fibroblasts and their transformation into myofibroblasts
Time frame: two years
Constitute cellular models of different types of CGD for future physiopathological studies and therapeutic trials
Time frame: for years
Results and safety
The study was stopped early (reason given: insufficient recruitment). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Sep 2017.
- Background: PubMed 26210446O'Neill S, Brault J, Stasia MJ, Knaus UG. Genetic disorders coupled to ROS deficiency. Redox Biol. 2015 Dec;6:135-156. doi: 10.1016/j.redox.2015.07.009. Epub 2015 Jul 17.
- Background: PubMed 17237347Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 2007 Jan;87(1):245-313. doi: 10.1152/physrev.00044.2005.
- Background: PubMed 18292807Nakano Y, Longo-Guess CM, Bergstrom DE, Nauseef WM, Jones SM, Banfi B. Mutation of the Cyba gene encoding p22phox causes vestibular and immune defects in mice. J Clin Invest. 2008 Mar;118(3):1176-85. doi: 10.1172/JCI33835.
- Background: PubMed 19559404Schiavone S, Sorce S, Dubois-Dauphin M, Jaquet V, Colaianna M, Zotti M, Cuomo V, Trabace L, Krause KH. Involvement of NOX2 in the development of behavioral and pathologic alterations in isolated rats. Biol Psychiatry. 2009 Aug 15;66(4):384-92. doi: 10.1016/j.biopsych.2009.04.033. Epub 2009 Jun 26.
- Background: PubMed 25469316Brault J, Goutagny E, Telugu N, Shao K, Baquie M, Satre V, Coutton C, Grunwald D, Brion JP, Barlogis V, Stephan JL, Plantaz D, Hescheler J, Krause KH, Saric T, Stasia MJ. Optimized Generation of Functional Neutrophils and Macrophages from Patient-Specific Induced Pluripotent Stem Cells: Ex Vivo Models of X(0)-Linked, AR22(0)- and AR47(0)- Chronic Granulomatous Diseases. Biores Open Access. 2014 Dec 1;3(6):311-26. doi: 10.1089/biores.2014.0045.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Dominique PLANTAZ principal investigator
University Hospital, Grenoble
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing samples collection : hair and skin biopsy in people with Chronic Granulomatous Disease, run by University Hospital, Grenoble at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 29 Sep 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was stopped early (reason given: insufficient recruitment). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02926963, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Sep 2017.