Nature Medicine
- 12, 401 - 409 (2006)
Published online: 2 April 2006; | doi:10.1038/nm1393
Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1Marion G Ott1, 16, Manfred Schmidt2, 3, 4, 16, Kerstin Schwarzwaelder3, 4, 5, 16, Stefan Stein6, 16, Ulrich Siler7, 16, Ulrike Koehl8, Hanno Glimm2, 3, Klaus Kühlcke9, Andrea Schilz9, Hana Kunkel6, Sonja Naundorf9, Andrea Brinkmann8, Annette Deichmann3, 4, Marlene Fischer2, 3, 5, Claudia Ball3, 4, 5, Ingo Pilz3, 5, Cynthia Dunbar10, Yang Du11, Nancy A Jenkins11, Neal G Copeland11, Ursula Lüthi12, Moustapha Hassan13, Adrian J Thrasher14, Dieter Hoelzer1, Christof von Kalle2, 3, 4, 15, 16, Reinhard Seger7, 16 & Manuel Grez6, 161
Department of Hematology/Oncology, University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. 2
Department of Internal Medicine I, University Hospital, Hugstetterstrasse 55, 79106 Freiburg, Germany. 3
Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Stefan-Meier-Strasse 17, 79104 Freiburg. Germany. 4
National Center for Tumor Diseases, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany. 5
Faculty of Biology, Albert-Ludwigs-University, Schaenzlestrasse 1, 79104 Freiburg, Germany. 6
Institute for Biomedical Research, Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42, 60596 Frankfurt, Germany. 7
Division of Immunology/Hematology, University Children's Hospital, Steinwiesstrasse 75, 8032 Zürich, Switzerland. 8
Pediatric Hematology, Oncology and Hemostaseology, University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. 9
European Institute for Research and Development of Transplantation Strategies (EUFETS) AG, Vollmersbachstrasse 66, 55743 Idar-Oberstein, Germany. 10
Hematology Branch, National Heart, Lung, and Blood Institute, 9000 Rockville Pike, Bethesda, Maryland 20892, USA. 11
Mouse Cancer Genetics Program, National Cancer Institute, Center for Cancer Research, 1050 Boyles Street, Frederick, Maryland 21702, USA. 12
Central Laboratory of Electron Microscopy, University of Zurich, Gloriastrasse 30, 8006 Zürich, Switzerland. 13
Department of Medicine, Division of Hematology, Karolinska Institute, SE-17177 Stockholm, Sweden. 14
Molecular Immunology Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. 15
Cincinnati Children's Research Foundation, Molecular and Gene Therapy Program, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA. 16
M.G.O., M.S., K.S., S.S. and U.S. contributed equally to this work; C.v.K., R.S. and M.G. share senior authorship.
Correspondence should be addressed to Manuel Grez grez@em.uni-frankfurt.de or Christof von Kalle christof.kalle@nct-heidelberg.de Gene transfer into hematopoietic stem cells has been used successfully for correcting lymphoid but not myeloid immunodeficiencies. Here we report on two adults who received gene therapy after nonmyeloablative bone marrow conditioning for the treatment of X-linked chronic granulomatous disease (X-CGD), a primary immunodeficiency caused by a defect in the oxidative antimicrobial activity of phagocytes resulting from mutations in gp91phox. We detected substantial gene transfer in both individuals' neutrophils that lead to a large number of functionally corrected phagocytes and notable clinical improvement. Large-scale retroviral integration site–distribution analysis showed activating insertions in MDS1-EVI1, PRDM16 or SETBP1 that had influenced regulation of long-term hematopoiesis by expanding gene-corrected myelopoiesis three- to four-fold in both individuals. Although insertional influences have probably reinforced the therapeutic efficacy in this trial, our results suggest that gene therapy in combination with bone marrow conditioning can be successfully used to treat inherited diseases affecting the myeloid compartment such as CGD.
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