Clinical trial NCT01906541: 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
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: X-linked Chronic Granulomatous Disease
Keywords: X-CGD
chronic granulomatous disease
gene-therapy
Lead sponsor: Johann Wolfgang Goethe University Hospital
Sponsor class: OTHER
First posted: 2013-07-24
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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)

Primary outcomes:
measure: Transduction rate of granulocyte colony-stimulating factor (G-CSF) mobilized peripheral CD34+ cells from CGD patients with a SIN gamma retroviral vector
timeFrame: 1 week
measure: Engraftment rate of the transduced CD34+ cells in the patients
timeFrame: 5 years
measure: Long-term expression of the transgene (rate of gp91phox positive cells) in circulating cells in the peripheral blood
timeFrame: 5 years
measure: Functional reconstitution of the NADPH oxidase in circulating cells of the peripheral blood (% DHR positive cells)
timeFrame: 5 years
measure: Frequency and severity of unexpected toxic adverse events during and after infusion of the genetically modified CD34+ cells
timeFrame: 5 years
Secondary outcomes:
measure: Frequency of infections as indicator for the clinical benefit for the patients
timeFrame: 5 years
measure: Proliferation rate of CD34+ cells in ex-vivo culture under serum-free conditions
timeFrame: up to 3 weeks
measure: Differentiation rate of CD34+ cells (as measured by flow cytometry) in ex-vivo culture under serum-free conditions
timeFrame: up to 3 weeks
measure: Transduction rate of CD34+ cells in ex-vivo culture under serum-free conditions
timeFrame: up to 12 weeks
Other outcomes:
Locations:
city: Frankfurt am Main
country: Germany
facility: University Hospital Frankfurt
Study officials:
References: