Design of a regulated lentiviral vector for hematopoietic stem cell gene therapy of globoid cell leukodystrophy
Globoid cell leukodystrophy (GLD) is a demyelinating lysosomal storage disease due to the deficiency of the galactocerebrosidase (GALC) enzyme. The favorable outcome of hematopoietic stem and progenitor cell (HSPC)-based approaches in GLD and other similar diseases suggests HSPC gene therapy as a pr...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2015-01-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S232905011630050X |
| _version_ | 1828340186675675136 |
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| author | Silvia Ungari Annita Montepeloso Francesco Morena Fabienne Cocchiarella Alessandra Recchia Sabata Martino Bernhard Gentner Luigi Naldini Alessandra Biffi |
| author_facet | Silvia Ungari Annita Montepeloso Francesco Morena Fabienne Cocchiarella Alessandra Recchia Sabata Martino Bernhard Gentner Luigi Naldini Alessandra Biffi |
| author_sort | Silvia Ungari |
| collection | DOAJ |
| description | Globoid cell leukodystrophy (GLD) is a demyelinating lysosomal storage disease due to the deficiency of the galactocerebrosidase (GALC) enzyme. The favorable outcome of hematopoietic stem and progenitor cell (HSPC)-based approaches in GLD and other similar diseases suggests HSPC gene therapy as a promising therapeutic option for patients. The path to clinical development of this strategy was hampered by a selective toxicity of the overexpressed GALC in the HSPC compartment. Here, we presented the optimization of a lentiviral vector (LV) in which miR-126 regulation was coupled to codon optimization of the human GALC cDNA to obtain a selective and enhanced enzymatic activity only upon transduced HSPCs differentiation. The safety of human GALC overexpression driven by this LV was extensively demonstrated in vitro and in vivo on human HSPCs from healthy donors. No perturbation in the content of proapoptotic sphingolipids, gene expression profile, and capability of engraftment and mutlilineage differentiation in chimeric mice was observed. The therapeutic potential of this LV was then assessed in a severe GLD murine model that benefited from transplantation of corrected HSPCs with longer survival and ameliorated phenotype as compared to untreated siblings. This construct has thus been selected as a candidate for clinical translation. |
| first_indexed | 2024-04-13T22:52:31Z |
| format | Article |
| id | doaj.art-93207bfde21d4b7fa5e8fe05ea3958f2 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-04-13T22:52:31Z |
| publishDate | 2015-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-93207bfde21d4b7fa5e8fe05ea3958f22022-12-22T02:26:08ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012015-01-012Design of a regulated lentiviral vector for hematopoietic stem cell gene therapy of globoid cell leukodystrophySilvia Ungari0Annita Montepeloso1Francesco Morena2Fabienne Cocchiarella3Alessandra Recchia4Sabata Martino5Bernhard Gentner6Luigi Naldini7Alessandra Biffi8San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, ItalySan Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, ItalyDepartment of Experimental Medicine and Biochemical Science, Perugia University, ItalyCenter for Regenerative Medicine âStefano Ferrari,â Department of Life Sciences, University of Modena and Reggio Emilia, Modena, ItalyCenter for Regenerative Medicine âStefano Ferrari,â Department of Life Sciences, University of Modena and Reggio Emilia, Modena, ItalyDepartment of Experimental Medicine and Biochemical Science, Perugia University, ItalySan Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, ItalySan Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, ItalySan Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, ItalyGloboid cell leukodystrophy (GLD) is a demyelinating lysosomal storage disease due to the deficiency of the galactocerebrosidase (GALC) enzyme. The favorable outcome of hematopoietic stem and progenitor cell (HSPC)-based approaches in GLD and other similar diseases suggests HSPC gene therapy as a promising therapeutic option for patients. The path to clinical development of this strategy was hampered by a selective toxicity of the overexpressed GALC in the HSPC compartment. Here, we presented the optimization of a lentiviral vector (LV) in which miR-126 regulation was coupled to codon optimization of the human GALC cDNA to obtain a selective and enhanced enzymatic activity only upon transduced HSPCs differentiation. The safety of human GALC overexpression driven by this LV was extensively demonstrated in vitro and in vivo on human HSPCs from healthy donors. No perturbation in the content of proapoptotic sphingolipids, gene expression profile, and capability of engraftment and mutlilineage differentiation in chimeric mice was observed. The therapeutic potential of this LV was then assessed in a severe GLD murine model that benefited from transplantation of corrected HSPCs with longer survival and ameliorated phenotype as compared to untreated siblings. This construct has thus been selected as a candidate for clinical translation.http://www.sciencedirect.com/science/article/pii/S232905011630050X |
| spellingShingle | Silvia Ungari Annita Montepeloso Francesco Morena Fabienne Cocchiarella Alessandra Recchia Sabata Martino Bernhard Gentner Luigi Naldini Alessandra Biffi Design of a regulated lentiviral vector for hematopoietic stem cell gene therapy of globoid cell leukodystrophy Molecular Therapy: Methods & Clinical Development |
| title | Design of a regulated lentiviral vector for hematopoietic stem cell gene therapy of globoid cell leukodystrophy |
| title_full | Design of a regulated lentiviral vector for hematopoietic stem cell gene therapy of globoid cell leukodystrophy |
| title_fullStr | Design of a regulated lentiviral vector for hematopoietic stem cell gene therapy of globoid cell leukodystrophy |
| title_full_unstemmed | Design of a regulated lentiviral vector for hematopoietic stem cell gene therapy of globoid cell leukodystrophy |
| title_short | Design of a regulated lentiviral vector for hematopoietic stem cell gene therapy of globoid cell leukodystrophy |
| title_sort | design of a regulated lentiviral vector for hematopoietic stem cell gene therapy of globoid cell leukodystrophy |
| url | http://www.sciencedirect.com/science/article/pii/S232905011630050X |
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