Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1
| Autor: | Andrea Brinkmann, Ursula Lüthi, Andrea Schilz, Nancy A. Jenkins, Claudia R. Ball, Manuel Grez, Christof von Kalle, Kerstin Schwarzwaelder, Neal G. Copeland, Dieter Hoelzer, Ulrich Siler, Annette Deichmann, Cynthia E. Dunbar, Hana Kunkel, Marlene Fischer, Ulrike Koehl, Adrian J. Thrasher, Moustapha Hassan, K. Kühlcke, Stefan Stein, Hanno Glimm, Manfred Schmidt, Reinhard Seger, Marion Ott, Yang Du, Sonja Naundorf, Ingo H. Pilz |
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| Rok vydání: | 2006 |
| Předmět: |
Adult
Genetic Markers Myeloid Genetic Linkage Neutrophils Genetic enhancement Genetic Vectors Biology Granulomatous Disease Chronic General Biochemistry Genetics and Molecular Biology Chronic granulomatous disease Proto-Oncogenes medicine Humans RNA Messenger Chromosomes Human X Clinical Trials as Topic Gene Transfer Techniques Nuclear Proteins Genetic Therapy General Medicine Hematopoietic Stem Cells medicine.disease MDS1 and EVI1 Complex Locus Protein Neoplasm Proteins DNA-Binding Proteins Mutagenesis Insertional Haematopoiesis Retroviridae Treatment Outcome medicine.anatomical_structure Immunology Primary immunodeficiency Bone marrow Myelopoiesis Stem cell Carrier Proteins Transcription Factors |
| Zdroj: | Nature Medicine. 12:401-409 |
| ISSN: | 1546-170X 1078-8956 |
| DOI: | 10.1038/nm1393 |
| Popis: | 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 gp91(phox). 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. |
| Databáze: | OpenAIRE |
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