Study of Gene Therapy Using a Lentiviral Vector to Treat X-linked Chronic Granulomatous Disease
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 trails 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.
|Granulomatous Disease, Chronic, X-linked||Biological: Lentiviral G1XCGD Gene Therapy||Phase 1 Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: 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|
- Evaluation of safety [ Time Frame: 2 years ]Safety of the procedure will be measured by the incidence of adverse events.
|Study Start Date:||January 2015|
|Estimated Study Completion Date:||December 2019|
|Estimated Primary Completion Date:||December 2018 (Final data collection date for primary outcome measure)|
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)
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02234934
|Contact: Caroline Y Kuo, MDemail@example.com|
|Contact: Kit L Shaw, MDfirstname.lastname@example.org|
|United States, California|
|University of California, Los Angeles (UCLA)||Recruiting|
|Los Angeles, California, United States, 90095|
|Contact: Caroline Y. Kuo, MD 310-794-1940 email@example.com|
|Principal Investigator: Caroline Y. Kuo, MD|
|Sub-Investigator: Satiro De Oliveira, MD|
|Sub-Investigator: Donald B. Kohn, MD|
|United States, Maryland|
|National Institutes of Health||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: Elizabeth Kang, MD 301-402-7567 firstname.lastname@example.org|
|Principal Investigator: Elizabeth Kang, MD|
|Sub-Investigator: Harry Malech, MD|
|Sub-Investigator: Suk See DeRavin, MD|
|United States, Massachusetts|
|Children's Hospital Boston||Recruiting|
|Boston, Massachusetts, United States, 90095|
|Contact: David A. Williams, MD 617-919-2697 DAWilliams@childrens.harvard.edu|
|Principal Investigator: David A. Williams, MD|
|Sub-Investigator: Leo Wang, MD, PhD|
|Sub-Investigator: Peter E. Newburger, MD|
|Principal Investigator:||Donald B. Kohn, MD||University of California, Los Angeles (UCLA)|
|Study Chair:||Caroline Y. Kuo, MD||University of California, Los Angeles (UCLA)|