Gene Therapy for X-CGD

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I/II Gene Therapy Trial for X-CGD With a SIN Gammaretroviral Vector

Conditions
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X-linked Chronic Granulomatous Disease

Intervention / Treatment
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* Genetic: ex-vivo gene-therapy


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ex-vivo gene-therapy<br>transplantation of genetically modified autologous CD34+ cells | Genetic: ex-vivo gene-therapy<br>* transplantation autologous CD34+ cells, transduced with a SIN gammaretroviral vector<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transduction rate of granulocyte colony-stimulating factor (G-CSF) mobilized peripheral CD34+ cells from CGD patients with a SIN gamma retroviral vector |  | 1 week | 
| Engraftment rate of the transduced CD34+ cells in the patients |  | 5 years | 
| Long-term expression of the transgene (rate of gp91phox positive cells) in circulating cells in the peripheral blood |  | 5 years | 
| Functional reconstitution of the NADPH oxidase in circulating cells of the peripheral blood (% DHR positive cells) |  | 5 years | 
| Frequency and severity of unexpected toxic adverse events during and after infusion of the genetically modified CD34+ cells |  | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of infections as indicator for the clinical benefit for the patients |  | 5 years | 
| Proliferation rate of CD34+ cells in ex-vivo culture under serum-free conditions |  | up to 3 weeks | 
| Differentiation rate of CD34+ cells (as measured by flow cytometry) in ex-vivo culture under serum-free conditions |  | up to 3 weeks | 
| Transduction rate of CD34+ cells in ex-vivo culture under serum-free conditions |  | up to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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X-CGD, chronic granulomatous disease, gene-therapy