Gene Therapy for X-CGD
Primary Purpose
X-linked Chronic Granulomatous Disease
Status
Unknown status
Phase
Phase 1
Locations
Germany
Study Type
Interventional
Intervention
ex-vivo gene-therapy
Sponsored by
About this trial
This is an interventional treatment trial for X-linked Chronic Granulomatous Disease focused on measuring X-CGD, chronic granulomatous disease, gene-therapy
Eligibility Criteria
Inclusion Criteria:
- Verified diagnosis of the X-linked form of chronic granulomatous disease, with loss of gp91phox expression (Western Blot). Evidence of less than 5% of normal oxidase production in circulating neutrophil granulocytes as measured by dihydrorhodamine- (DHR-) and nitro blue tetrazolium- (NBT-) assay
- History of severe chronic infections with life-threatening course or severe steroid- sensitive or steroid insensitive granulomatous disease, with necessity of inpatient treatment, without sustained improvement even under maximum conservative treatment measures
- No Human Leukocyte Antigen (HLA) identical (10/10 match) sibling- or unrelated donor, or contraindications for allogenic stem cell transplantation in presence of a suitable donor. The lack of an HLA-identical (10/10 match) sibling- or unrelated donor has to be confirmed by an unsuccessful search in national and international donor registers for at leat 3 months
- Normal organ-function: glomerular filtration rate (GFR) ≥ 60ml/min., Bilirubin ≤ 1.5-fold upper reference-level, normal parameters for liver enzymes and clotting (TPZ 75-100%, partial thromboplastin time (PTT) 30-38sec, Fibrinogen 200-400mg/dl), Leukocytes > 3 x 10^9/l, Granulocytes > 1.5 x 10^9/l, Thrombocytes >100 x 10^9/l
- Contraception from start of G-CSF application until 1 year after retransfusion of the gene-corrected cells
- No interferon-gamma injection within two weeks prior to hematopoietic stem cell mobilization
- Karnofsky-Index > 70%
- Signed informed consent
Exclusion Criteria:
- Patients with non-controlled acute infections
- Severe cardiac or pulmonary malfunctions: ejection fraction < 60%, valvular heart disease > II°, arrhythmia requiring therapy, forced expiratory volume at one second/vital capacity (FEV1/VC) < 75% , diffusion capacity of lung for carbon monoxide (DLCO) <60%
- Bilirubin > 1.5-fold upper reference-level
- HIV-, Hepatitis B- or C - infection
- Contraindications for G-CSF administration, as autoimmune vasculitis.
- Contraindications for stem cell apheresis, as low hemoglobin < 8g/dl, cardiovascular instability or severe coagulopathy
- Pregnancy or breast-feeding
- Drug- or alcohol-abuse
- Lack of search for an unrelated donor
- Patients with a HLA 9/10 mismatched unrelated donor (MMUD) will be excluded, if a thorough risk-benefit analysis favors allogenic hematopoietic stem cell transplantation (HSCT)
Sites / Locations
- University Hospital FrankfurtRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
ex-vivo gene-therapy
Arm Description
transplantation of genetically modified autologous CD34+ cells
Outcomes
Primary Outcome Measures
Transduction rate of granulocyte colony-stimulating factor (G-CSF) mobilized peripheral CD34+ cells from CGD patients with a SIN gamma retroviral vector
Engraftment rate of the transduced CD34+ cells in the patients
Long-term expression of the transgene (rate of gp91phox positive cells) in circulating cells in the peripheral blood
Functional reconstitution of the NADPH oxidase in circulating cells of the peripheral blood (% DHR positive cells)
Frequency and severity of unexpected toxic adverse events during and after infusion of the genetically modified CD34+ cells
Secondary Outcome Measures
Frequency of infections as indicator for the clinical benefit for the patients
Proliferation rate of CD34+ cells in ex-vivo culture under serum-free conditions
Differentiation rate of CD34+ cells (as measured by flow cytometry) in ex-vivo culture under serum-free conditions
Transduction rate of CD34+ cells in ex-vivo culture under serum-free conditions
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01906541
Brief Title
Gene Therapy for X-CGD
Official Title
A Phase I/II Gene Therapy Trial for X-CGD With a SIN Gammaretroviral Vector
Study Type
Interventional
2. Study Status
Record Verification Date
August 2013
Overall Recruitment Status
Unknown status
Study Start Date
July 2013 (undefined)
Primary Completion Date
December 2013 (Anticipated)
Study Completion Date
December 2019 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Hubert Serve, Prof., MD
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
X-linked chronic granulomatous disease (X-CGD) is a rare inherited immune defect, which is caused by the inability of phagocytic cells to produce reactive oxygen species due to a defect in the gp91phox subunit of the NADPH oxidase complex. X-CGD patients suffer from recurrent and life-threatening infections and severe hyperinflammatory complications.
The only curative treatment for X-CGD is allogenic hematopoietic stem cell transplantation, but this procedure implies severe risks and many patients lack an appropriate donor. Therefore alternative curative approaches are urgently needed. In this study, patients will be treated with gene-corrected autologous CD34+ cells, using a SIN gammaretroviral vector for ex-vivo gene-therapy.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
X-linked Chronic Granulomatous Disease
Keywords
X-CGD, chronic granulomatous disease, gene-therapy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
5 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
ex-vivo gene-therapy
Arm Type
Experimental
Arm Description
transplantation of genetically modified autologous CD34+ cells
Intervention Type
Genetic
Intervention Name(s)
ex-vivo gene-therapy
Intervention Description
transplantation autologous CD34+ cells, transduced with a SIN gammaretroviral vector
Primary Outcome Measure Information:
Title
Transduction rate of granulocyte colony-stimulating factor (G-CSF) mobilized peripheral CD34+ cells from CGD patients with a SIN gamma retroviral vector
Time Frame
1 week
Title
Engraftment rate of the transduced CD34+ cells in the patients
Time Frame
5 years
Title
Long-term expression of the transgene (rate of gp91phox positive cells) in circulating cells in the peripheral blood
Time Frame
5 years
Title
Functional reconstitution of the NADPH oxidase in circulating cells of the peripheral blood (% DHR positive cells)
Time Frame
5 years
Title
Frequency and severity of unexpected toxic adverse events during and after infusion of the genetically modified CD34+ cells
Time Frame
5 years
Secondary Outcome Measure Information:
Title
Frequency of infections as indicator for the clinical benefit for the patients
Time Frame
5 years
Title
Proliferation rate of CD34+ cells in ex-vivo culture under serum-free conditions
Time Frame
up to 3 weeks
Title
Differentiation rate of CD34+ cells (as measured by flow cytometry) in ex-vivo culture under serum-free conditions
Time Frame
up to 3 weeks
Title
Transduction rate of CD34+ cells in ex-vivo culture under serum-free conditions
Time Frame
up to 12 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Verified diagnosis of the X-linked form of chronic granulomatous disease, with loss of gp91phox expression (Western Blot). Evidence of less than 5% of normal oxidase production in circulating neutrophil granulocytes as measured by dihydrorhodamine- (DHR-) and nitro blue tetrazolium- (NBT-) assay
History of severe chronic infections with life-threatening course or severe steroid- sensitive or steroid insensitive granulomatous disease, with necessity of inpatient treatment, without sustained improvement even under maximum conservative treatment measures
No Human Leukocyte Antigen (HLA) identical (10/10 match) sibling- or unrelated donor, or contraindications for allogenic stem cell transplantation in presence of a suitable donor. The lack of an HLA-identical (10/10 match) sibling- or unrelated donor has to be confirmed by an unsuccessful search in national and international donor registers for at leat 3 months
Normal organ-function: glomerular filtration rate (GFR) ≥ 60ml/min., Bilirubin ≤ 1.5-fold upper reference-level, normal parameters for liver enzymes and clotting (TPZ 75-100%, partial thromboplastin time (PTT) 30-38sec, Fibrinogen 200-400mg/dl), Leukocytes > 3 x 10^9/l, Granulocytes > 1.5 x 10^9/l, Thrombocytes >100 x 10^9/l
Contraception from start of G-CSF application until 1 year after retransfusion of the gene-corrected cells
No interferon-gamma injection within two weeks prior to hematopoietic stem cell mobilization
Karnofsky-Index > 70%
Signed informed consent
Exclusion Criteria:
Patients with non-controlled acute infections
Severe cardiac or pulmonary malfunctions: ejection fraction < 60%, valvular heart disease > II°, arrhythmia requiring therapy, forced expiratory volume at one second/vital capacity (FEV1/VC) < 75% , diffusion capacity of lung for carbon monoxide (DLCO) <60%
Bilirubin > 1.5-fold upper reference-level
HIV-, Hepatitis B- or C - infection
Contraindications for G-CSF administration, as autoimmune vasculitis.
Contraindications for stem cell apheresis, as low hemoglobin < 8g/dl, cardiovascular instability or severe coagulopathy
Pregnancy or breast-feeding
Drug- or alcohol-abuse
Lack of search for an unrelated donor
Patients with a HLA 9/10 mismatched unrelated donor (MMUD) will be excluded, if a thorough risk-benefit analysis favors allogenic hematopoietic stem cell transplantation (HSCT)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Hubert Serve, Prof., MD
Phone
0049/69/6301
Ext
4634
Email
serve@em.uni-frankfurt.de
First Name & Middle Initial & Last Name or Official Title & Degree
Joachim Schwäble, MD
Phone
0049/69/67824900
Email
schwaeble@em.uni-frankfurt.de
Facility Information:
Facility Name
University Hospital Frankfurt
City
Frankfurt am Main
ZIP/Postal Code
60595
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Joachim Schwäble, MD
Phone
0049/69 /67824900
Email
schwaeble@em.uni-frankfurt.de
12. IPD Sharing Statement
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Gene Therapy for X-CGD
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