Abstract for presentation at 11th International Congress of Human Genetics

Correction of Chronic Granulomatous Disease by gene therapy: Results from a Phase I clinical trial

  • Manuel Grez, Institute for Biomedical Research, Georg-Speyer-Haus, Frankfurt, Germany
  • Marion Ott, Dept. of Hematology, Medical School, Frankfurt, Germany
  • Manfred Schmidt, National Center for Tumor Diseases, Heidelberg, Germany
  • Stefan Stein, Institute for Biomedical Research, Georg-Speyer-Haus, Frankfurt, Germany
  • Ulli Siler, Division of Immunology/Hematology, Children Hospital Zurich, Switzerland
  • Christof von Kalle, National Center for Tumor Diseases, Heidelberg, Germany
  • Dieter Hoelzer, Dept. of Hematology, Medical School, Frankfurt, Germany
  • Reinhard Seger, Division of Immunology/Hematology, Children Hospital Zurich, Switzerland

    • Chronic Granulomatous Disease (CGD) is a rare inherited immunodeficiency caused by a functional defect in the microbial killing activity of phagocytes. CGD is caused by mutations or deletions in any of four genes encoding for essential subunits of the phagocytic NADPH oxidase complex (gp91phox, p22phox, p47phox and p67phox). Almost 60% of CGD patients contain defects in the X-linked gene encoding for gp91phox. Although the disease can be cure by bone marrow transplantation, this treatment is recommended only to patients with HLA-identical sibling or matched unrelated donors. One therapeutic option for CGD patients is the genetic modification of autologous bone marrow stem cells. Although CGD has been successfully corrected in animal models by gene transfer into hematopoietic stem cells similar successes have been difficult to achieve in unconditioned CGD patients.
    Based on our preclinical work, two X-CGD patients, 26 and 25 years old, were treated with gene modified cells. G-CSF mobilized peripheral blood CD34+ cells were collected, transduced with a monocistronic gammaretroviral vector expressing gp91phox and reinfused into the patients 5 days later. Previous to reinfusion, liposomal busulfan (L-Bu) was administered intravenously on days –3 and -2 at a dose of 4 mg/kg/day. A significant fraction of gene marked cells (>20%) were detected within the first 4-5 months after transplantation. Thereafter a continuous increase in the number of gene modified cells was observed with almost identical kinetics in both patients. This increase was caused by transcriptional upregulation of three genes previously known to be involved in cell cycle progression. Importantly this expansion did not result in neutrophil counts above those seen before gene therapy. Therapeutic relevant levels of NADPH oxidase activity were achieved in both patients leading to the elimination of therapy refractory bacterial and fungal infections. Our data suggests that gene therapy is an option for the treatment of CGD.

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