Ignite Creation Date:
2024-05-06 @ 3:13 AM
Last Modification Date:
2024-10-26 @ 11:30 AM
Study NCT ID:
NCT02234934
Status:
RECRUITING
Last Update Posted:
2023-11-18
First Post:
2014-09-04
Brief Title:
Study of Gene Therapy Using a Lentiviral Vector to Treat X-linked Chronic Granulomatous Disease
Sponsor:
University of California Los Angeles
Organization:
University of California Los Angeles
Study Overview
Official Title:
A Two-Part Phase III Non Randomized Multicenter Open-Label Study of G1XCGD Lentiviral Vector Transduced CD34 Cells in Patients With X-Linked Chronic Granulomatous Disease
Status:
RECRUITING
Status Verified Date:
2023-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 200000 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 two-part prospective non-controlled non-randomized Phase III 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 3-6 patients will be treated per site with a goal of 16 total patients to be treated with G1XCGD lentiviral vector
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 two-part prospective non-controlled non-randomized Phase III 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 3-6 patients will be treated per site with a goal of 16 total patients to be treated with G1XCGD lentiviral vector
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 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 CEBP and PU1 from 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 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
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 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 CEBP and PU1 from 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 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2P01HL073104 | NIH | None | httpsreporternihgovquickSearch2P01HL073104 |