We updated the design of this site on December 18, 2017. Learn more.
ClinicalTrials.gov Menu
Trial record 1 of 4 for:    chronic granulomatous disease AND Los Angeles
Previous Study | Return to List | Next Study

Study of Gene Therapy Using a Lentiviral Vector to Treat X-linked Chronic Granulomatous Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02234934
Recruitment Status : Suspended (Serious Adverse Event, under review)
First Posted : September 9, 2014
Last Update Posted : November 8, 2017
Information provided by (Responsible Party):

Study Description
Brief Summary:

Chronic Granulomatous Disease (CGD) is an inherited immunodeficiency disorder which results from defects that prevent white blood cells from effectively killing bacteria, fungi and other microorganisms. Chronic granulomatous inflammation may compromise vital organs and account for additional morbidity. CGD is thought to affect approximately 1 in 200,000 persons, although the real incidence might be higher due to under-diagnosis of milder phenotypes.

The first gene therapy approaches in X-CGD have shown that effective gene therapy requires bone-marrow (BM) conditioning with chemotherapy to make space for the gene-modified cells to engraft. These studies demonstrated that transplantation of gene modified stem cells led to production of white blood cells that could clear existing infections. However, some trials using mouse-derived retroviral vectors were complicated by the development of myelodysplasia and leukemia-like growth of blood cells. This trial will evaluate a new lentiviral vector that may be able to correct the defect, but have much lower risk for the complication.

This study is a prospective non-controlled, non-randomized Phase I/II clinical trial to assess the safety, feasibility and efficacy of cellular gene therapy in patients with chronic granulomatous disease using transplantation of autologous bone marrow CD34+ cells transduced ex vivo by the G1XCGD lentiviral vector containing the human CGD gene. Primary objectives include evaluation of safety and evaluation of efficacy by biochemical and functional reconstitution in progeny of engrafted cells and stability at 12 months. Secondary objectives include evaluation of clinical efficacy, longitudinal evaluation of clinical effect in terms of augmented immunity against bacterial and fungal infection, transduction of CD34+ hematopoietic cells from X-CGD patients by ex vivo lentivirus-mediated gene transfer, and evaluation of engraftment kinetics and stability. Approximately 3-5 patients will be treated per site with a goal of 10 total patients to be treated with G1XCGD lentiviral vector.

Condition or disease Intervention/treatment Phase
Granulomatous Disease, Chronic, X-linked Biological: Lentiviral G1XCGD Gene Therapy Phase 1 Phase 2

Detailed Description:

The therapeutic product to be evaluated is autologous CD34+ hematopoietic stem cells (HSC) modified by ex vivo transduction using the pCCLchimGP91WPRE lentiviral vector (G1XCGD Modified Autologous BM CD34 cells) containing the human CGD gene. The G1XCGD lentiviral vector is a 3rd generation self-inactivating lentiviral vector which directs gp91phox expression from a codon-optimized form of the CYBB gene preferentially to myeloid cells, with a modified WPRE (PRE4).

G1XCGD is an integrative, 3rd generation replication-defective, self-inactivating (SIN) HIV-derived Lentiviral (LV) vector, with a mutated Woodchuck hepatitis virus Posttranscriptional Regulatory Element (WPRE) sequence. (Figure 1) A LV vector derived from HIV-1 has been chosen with respect to LV natural properties: they are genetically stable, permanently integrate into the genome of transduced cells and provide long-term gene expression in vitro and in vivo. The transduction of Hematopoietic Stem Cells (HSC) with such LV can be achieved after limited pre-activation of the cells in short-term cultures with cytokines, in conditions that are compatible with the preservation of the self-renewing capacities of these cells. These properties make these LV suitable for ex-vivo gene therapy strategies using HSC.

G1XCGD provirus includes a chimeric promoter designed to regulate the transgene expression in myeloid cells and a transgene called GP91 (also known as CYBB), which is a codon-optimized cDNA sequence of the human CYBB gene also known as GP91-PHOX or NOX2 gene: The promoter is a synthetic chimeric element created by the fusion of c-Fes and Cathepsin G minimal 5'-flanking regions. Cathepsin G is a serine protease stored in the azurophil granules of neutrophil granulocytes. Part of the chimeric promoter contains binding sites for myeloid transcription factors C/EBP and PU.1from the upstream region of the transcription start site of the Cathepsin G gene. The other part of the chimeric promoter is a human c-Fes sequence that has been added to enhance the Cathepsin G promoter activity in granulocytic cells. The resulting chimeric promoter is able to i) regulate the expression of the GP91 transgene by in myeloid cells in a specific manner and ii) to effectively restore NADPH-oxidase activity in granulocytes, as reported by Santilli et al. (Santilli et al., 2011) and confirmed in preclinical studies conducted with the G1XCGD vector. The GP91 transgene codes for the 570 amino-acid cytochrome b-245, a 91 kD beta polypeptide that is also known as the NADPH-oxidase catalytic subunit gp91-phox, or cytochrome b-245 heavy chain, or gp91-phox protein.

Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II, Non Randomized, Multicenter, Open-Label Study of G1XCGD (Lentiviral Vector Transduced CD34+ Cells) in Patients With X-Linked Chronic Granulomatous Disease
Study Start Date : January 2015
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2019

Arms and Interventions

Arm Intervention/treatment
Experimental: Lentiviral G1XCGD Gene Therapy
Transplantation with autologous CD34+ stem cells corrected with X1XCGD lentiviral vector after myeloreductive conditioning
Biological: Lentiviral G1XCGD Gene Therapy

The investigational product is patient-specific and corresponds to autologous CD34+ cells transduced ex vivo with the G1XCGD vector in their final suspension. The starting materials used for the production of the investigational product consist of the viral vector and the patient's CD34+ cells.

The G1XCGD vector is used to transduce autologous CD34+ cells ex vivo. These transduced cells are then infused into the patient. The cell/product dose will consist of at least 1 x 10^6 cells per kg of body weight transduced ex vivo with 1 x 10^8 IG/ml of lentiviral vector to achieve > 0.3 integrated copies per cell.

Other Name: G1XCGD (pCCLChimGp91/VSVg lentiviral vector)

Outcome Measures

Primary Outcome Measures :
  1. Evaluation of safety [ Time Frame: 2 years ]
    Safety of the procedure will be measured by the incidence of adverse events.

Eligibility Criteria

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:   23 Months and older   (Child, Adult, Senior)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Male X-CGD patients > 23 months of age
  • Molecular diagnosis confirmed by DNA sequencing and supported by laboratory evidence for absent or reduction > 95% of the biochemical activity of the NADPH-oxidase
  • At least one prior, ongoing or refractory severe infection and/or inflammatory complications requiring hospitalization despite conventional therapy
  • No 10/10 HLA-matched donor available after searching of NMDP registries
  • No co-infection with Human Immunodeficiency Virus (HIV) or hepatitis B virus (HBsAg positive) or hepatitis C virus (HCV RNA positive), CMV, adenovirus, parvovirus B 19 or toxoplasmosis
  • Written informed consent for adult patient, and assent for pediatric subjects seven years or older.
  • Parental/guardian and, where appropriate, child's signed consent/assent

Exclusion Criteria:

  • Age < 23 months
  • 10/10 HLA identical (A,B,C,DR,DQ) family or unrelated or cord blood donor unless there is deemed to be an unacceptable risk associated with an allogeneic procedure
  • Contraindication for leukapheresis or bone marrow harvest (anemia Hb <8g/dl, cardiovascular instability, severe coagulopathy)
  • Appropriate organ function as outlined below must be observed within 8 weeks of entering this trial.

    1. Hematologic

      1. Anemia (hemoglobin < 8 g/dl).
      2. Neutropenia (absolute granulocyte count <1,000/mm3)
      3. Thrombocytopenia (platelet count < 150,000/mm3).
      4. PT or PTT > 2X the upper limits of normal (patients with a correctable deficiency controlled on medication will not be excluded).
      5. Cytogenetic abnormalities known to be associated with hematopoietic defect on peripheral blood or bone marrow.
    2. Infectious

      a. Evidence of active infection with HIV-1, hepatitis B, Hepatitis C, CMV, adenovirus, parvovirus B19 or toxoplasmosis by DNA PCR within 8 weeks prior to mobilization/pheresis or bone marrow harvest.

    3. Pulmonary

      a. Resting O2 saturation by pulse oximetry < 90% on room air.

    4. Cardiac

      1. Abnormal electrocardiogram (EKG) indicating cardiac pathology.
      2. Uncorrected congenital cardiac malformation with clinical symptomatology.
      3. Active cardiac disease, including clinical evidence of congestive heart failure, cyanosis, hypotension.
      4. Poor cardiac function as evidenced by LV ejection fraction < 40% on echocardiogram.
    5. Neurologic

      1. Significant neurologic abnormality by examination.
      2. Uncontrolled seizure disorder.
    6. Renal

      1. Renal insufficiency: serum creatinine ≥ 1.5 mg/dl, or ≥ 3+ proteinuria.
      2. Abnormal serum sodium, potassium, calcium, magnesium, phosphate at grade III or IV by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
    7. Hepatic/GI:

      1. Serum transaminases > 5X the upper limit of normal (ULN).
      2. Serum bilirubin > 2X ULN.
      3. Serum glucose > 1.5x ULN.
    8. Oncologic

      a. Evidence of active malignant disease

    9. General

      1. Expected survival < 6 months
      2. Major congenital anomaly
      3. Ineligible for autologous HSCT by the criteria at the clinical site.
      4. Contraindication for administration of conditioning medication. (Known sensitivity to Busulfan)
      5. Administration of gamma-interferon within 30 days before the infusion of transduced, autologous CD34+ cells.
      6. Participation in another experimental therapeutic protocol within 6 months prior to baseline and during the study period.
      7. Any other condition that, in the opinion of the Investigator, may compromise the safety or compliance of the patient or would preclude the patient from successful study completion.
      8. Patient/Parent/Guardian unable or unwilling to comply with the protocol requirements.
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02234934

United States, California
University of California, Los Angeles (UCLA)
Los Angeles, California, United States, 90095
United States, Maryland
National Institutes of Health
Bethesda, Maryland, United States, 20892
United States, Massachusetts
Children's Hospital Boston
Boston, Massachusetts, United States, 90095
Sponsors and Collaborators
University of California, Los Angeles
Boston Children’s Hospital
National Institute of Allergy and Infectious Diseases (NIAID)
California Institute for Regenerative Medicine
Principal Investigator: Donald B. Kohn, MD University of California, Los Angeles (UCLA)
Study Chair: Caroline Y. Kuo, MD University of California, Los Angeles (UCLA)
More Information

Responsible Party: Donald B. Kohn, M.D., Professor, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT02234934     History of Changes
Other Study ID Numbers: G1XCGD
First Posted: September 9, 2014    Key Record Dates
Last Update Posted: November 8, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Results will be published in scientific literature once trial is completed and data analysis is done.

Keywords provided by Donald B. Kohn, M.D., University of California, Los Angeles:
Gene Therapy
X-Linked Chronic Granulomatous Disease (X-CGD)
Lentiviral Vector

Additional relevant MeSH terms:
Chronic Disease
Granulomatous Disease, Chronic
Disease Attributes
Lymphoproliferative Disorders
Lymphatic Diseases
Leukocyte Disorders
Hematologic Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Immune System Diseases
Pathologic Processes
Phagocyte Bactericidal Dysfunction
Immunologic Deficiency Syndromes