Lineage- and stage-restricted lentiviral vectors for the gene therapy of chronic granulomatous disease
| Autor: | Sonia Verp, Didier Trono, Maciej Wiznerowicz, Elisa Laurenti, Isabelle Barde, A. Viornery, Sandra Offner, Anne Galy, Andreas Trumpp |
|---|---|
| Přispěvatelé: | Immunologie moléculaire et biothérapies innovantes (IMBI), Généthon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Évry-Val-d'Essonne (UEVE)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Généthon |
| Rok vydání: | 2011 |
| Předmět: |
[SDV]Life Sciences [q-bio]
Genetic enhancement Cellular differentiation Genetic Vectors Genetic Therapy/*methods Gene delivery Biology Granulomatous Disease Chronic Viral vector Mice 03 medical and health sciences 0302 clinical medicine Chronic granulomatous disease Receptors Genetics medicine Animals Vector (molecular biology) Receptors Immunologic Molecular Biology Gene 030304 developmental biology 0303 health sciences Chronic/*therapy Lentivirus Gene Transfer Techniques NADPH Oxidases Lentivirus/*genetics Genetic Therapy medicine.disease Virology Transplantation Granulocytes/metabolism 030220 oncology & carcinogenesis Cancer research [SDV.IMM]Life Sciences [q-bio]/Immunology Molecular Medicine Granulomatous Disease NADPH Oxidase/metabolism Immunologic/*genetics Granulocytes |
| Zdroj: | Gene Ther Gene Ther, 2011, 18 (11), pp.1087-97. ⟨10.1038/gt.2011.65⟩ Gene therapy Gene Therapy Gene Therapy, 2011, 18 (11), pp.1087-1097. ⟨10.1038/gt.2011.65⟩ |
| ISSN: | 1476-5462 0969-7128 |
| DOI: | 10.1038/gt.2011.65 |
| Popis: | International audience; Insertional mutagenesis represents a serious adverse effect of gene therapy with integrating vectors. However, although uncontrolled activation of growth-promoting genes in stem cells can predictably lead to oncological processes, this is far less likely if vector transcriptional activity can be restricted to fully differentiated cells. Diseases requiring phenotypic correction only in mature cells offer such an opportunity, provided that lineage/stage-restricted systems can be properly tailored. In this study, we followed this reasoning to design lentiviral vectors for the gene therapy of chronic granulomatous disease (CGD), an immune deficiency due a loss of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytes, most often secondary to mutations in gp91(phox). Using self-inactivating HIV1-derived vectors as background, we first expressed enhanced green fluorescent protein (eGFP) from a minimal gp91(phox) promoter, adding various natural or synthetic transcriptional regulatory elements to foster both specificity and potency. The resulting vectors were assessed either by transplantation or by lentiviral transgenesis, searching for combinations conferring strong and specific expression into mature phagocytic cells. The most promising vector was modified to express gp91(phox) and used to treat CGD mice. High-level restoration of NADPH activity was documented in granulocytes from the treated animals. We propose that this lineage-specific lentiviral vector is a suitable candidate for the gene therapy of CGD. |
| Databáze: | OpenAIRE |
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