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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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

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 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 b

Detailed Summary:

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
Sponsor: University of California, Los Angeles

Current Primary Outcome: Evaluation of safety [ Time Frame: 2 years ]

Safety of the procedure will be measured by the incidence of adverse events.


Original Primary Outcome:

  • Evaluation of safety [ Time Frame: 2 years ]
    Safety of the procedure will be measured by the incidence of adverse events.
  • Evaluation of efficacy [ Time Frame: 12 months ]
    An evaluation of efficacy will be based on biochemical and functional reconstitution in progeny of engrafted cells and transgene expression stability at 12 months. This includes restoration and stability over time of the NADPH functioning granulocytes assessed by dihydrorhodamine test (≥5 % of expressing cells at >20% of normal activity at 12 months)


Current Secondary Outcome:

Original Secondary Outcome:

  • Clinical Efficacy [ Time Frame: 2 years ]
    Clinical efficacy and longitudinal evaluation of clinical effect will be evaluated in terms of augmented immunity against bacterial and fungal infections. Clinical factors include normalization of nutritional status, growth, development (as appropriate for children and adolescents), severe infection and/or inflammatory complications existing prior to gene therapy.
  • Efficiency of CD34+ hematopoietic cell transduction [ Time Frame: 2 years ]
    The percentage of transduced CD34+ hematopoietic cells infused and of blood cells over time will be measured at months 1, 2, 3, 6, 9, 12, 18, and 24.
  • Immunologic reconstitution [ Time Frame: 2 years ]
    Immunologic reconstitution will be evaluated on the basis of restored neutrophil functionality and immunity against bacterial and fungal infections.


Information By: University of California, Los Angeles

Dates:
Date Received: September 4, 2014
Date Started: January 2015
Date Completion: December 2019
Last Updated: January 4, 2017
Last Verified: January 2017