A single adenovirus vector mediates doxycycline-controlled expression of tyrosine hydroxylase in brain grafts of human neural progenitors
Ex vivo gene transfer is emerging as a promising therapeutic approach to human neurodegenerative diseases. By combining efficient methodologies for cell amplification and gene delivery, large numbers of cells can be generated with the capacity to synthesize therapeutic molecules. These cells can the...
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Veröffentlicht in: | Nature biotechnology 1999-04, Vol.17 (4), p.349-354 |
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creator | Mallet, Jacques Corti, Olga Sabaté, Olivier Horellou, Philippe Colin, Philippe Dumas, Sylvie Buchet, Delphine Buc-Caron, Marie-Hélène |
description | Ex vivo gene transfer is emerging as a promising therapeutic approach to human neurodegenerative diseases. By combining efficient methodologies for cell amplification and gene delivery, large numbers of cells can be generated with the capacity to synthesize therapeutic molecules. These cells can then be transplanted into the degenerating central nervous system (CNS). Applying this approach to human diseases will require the development of suitable cellular vehicles, as well as safe gene delivery systems capable of tightly controlled transgene expression. For such brain repair technologies, human neural progenitors may be extremely valuable, because of their human CNS origin and developmental potential. We have used these cells to develop a system for the regulated expression of a gene of therapeutic potential. We report the construction of a single adenovirus encoding human tyrosine hydroxylase 1 (hTH-1) under the negative control of the tetracycline-based gene regulatory system. Human neural progenitors infected with this vector produced large amounts of hTH-1. Most importantly, doxycycline allowed a reversible switch of transgene transcription both in vitro and in vivo. This system may be applied to the development of therapies for human neurodegenerative diseases. |
doi_str_mv | 10.1038/7901 |
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By combining efficient methodologies for cell amplification and gene delivery, large numbers of cells can be generated with the capacity to synthesize therapeutic molecules. These cells can then be transplanted into the degenerating central nervous system (CNS). Applying this approach to human diseases will require the development of suitable cellular vehicles, as well as safe gene delivery systems capable of tightly controlled transgene expression. For such brain repair technologies, human neural progenitors may be extremely valuable, because of their human CNS origin and developmental potential. We have used these cells to develop a system for the regulated expression of a gene of therapeutic potential. We report the construction of a single adenovirus encoding human tyrosine hydroxylase 1 (hTH-1) under the negative control of the tetracycline-based gene regulatory system. Human neural progenitors infected with this vector produced large amounts of hTH-1. Most importantly, doxycycline allowed a reversible switch of transgene transcription both in vitro and in vivo. This system may be applied to the development of therapies for human neurodegenerative diseases.</description><identifier>ISSN: 1087-0156</identifier><identifier>EISSN: 1546-1696</identifier><identifier>DOI: 10.1038/7901</identifier><identifier>PMID: 10207882</identifier><identifier>CODEN: NABIF9</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>Adenoviridae - genetics ; Agriculture ; Animals ; Bioinformatics ; Biological and medical sciences ; Biomedical and Life Sciences ; Biomedical Engineering/Biotechnology ; Biomedicine ; Biotechnology ; Brain - cytology ; Brain - embryology ; Brain - enzymology ; Brain Tissue Transplantation ; Cell Transplantation ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; Doxycycline - pharmacology ; Fetal Tissue Transplantation ; Fundamental and applied biological sciences. Psychology ; Gene Expression Regulation ; Gene therapy ; Gene Transfer Techniques ; Genetic Vectors ; Health. Pharmaceutical industry ; Humans ; Industrial applications and implications. 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By combining efficient methodologies for cell amplification and gene delivery, large numbers of cells can be generated with the capacity to synthesize therapeutic molecules. These cells can then be transplanted into the degenerating central nervous system (CNS). Applying this approach to human diseases will require the development of suitable cellular vehicles, as well as safe gene delivery systems capable of tightly controlled transgene expression. For such brain repair technologies, human neural progenitors may be extremely valuable, because of their human CNS origin and developmental potential. We have used these cells to develop a system for the regulated expression of a gene of therapeutic potential. We report the construction of a single adenovirus encoding human tyrosine hydroxylase 1 (hTH-1) under the negative control of the tetracycline-based gene regulatory system. Human neural progenitors infected with this vector produced large amounts of hTH-1. Most importantly, doxycycline allowed a reversible switch of transgene transcription both in vitro and in vivo. This system may be applied to the development of therapies for human neurodegenerative diseases.</description><subject>Adenoviridae - genetics</subject><subject>Agriculture</subject><subject>Animals</subject><subject>Bioinformatics</subject><subject>Biological and medical sciences</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedical Engineering/Biotechnology</subject><subject>Biomedicine</subject><subject>Biotechnology</subject><subject>Brain - cytology</subject><subject>Brain - embryology</subject><subject>Brain - enzymology</subject><subject>Brain Tissue Transplantation</subject><subject>Cell Transplantation</subject><subject>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</subject><subject>Doxycycline - pharmacology</subject><subject>Fetal Tissue Transplantation</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene Expression Regulation</subject><subject>Gene therapy</subject><subject>Gene Transfer Techniques</subject><subject>Genetic Vectors</subject><subject>Health. Pharmaceutical industry</subject><subject>Humans</subject><subject>Industrial applications and implications. 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Leukodystrophies. Prion diseases</topic><topic>Doxycycline - pharmacology</topic><topic>Fetal Tissue Transplantation</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene Expression Regulation</topic><topic>Gene therapy</topic><topic>Gene Transfer Techniques</topic><topic>Genetic Vectors</topic><topic>Health. Pharmaceutical industry</topic><topic>Humans</topic><topic>Industrial applications and implications. 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By combining efficient methodologies for cell amplification and gene delivery, large numbers of cells can be generated with the capacity to synthesize therapeutic molecules. These cells can then be transplanted into the degenerating central nervous system (CNS). Applying this approach to human diseases will require the development of suitable cellular vehicles, as well as safe gene delivery systems capable of tightly controlled transgene expression. For such brain repair technologies, human neural progenitors may be extremely valuable, because of their human CNS origin and developmental potential. We have used these cells to develop a system for the regulated expression of a gene of therapeutic potential. We report the construction of a single adenovirus encoding human tyrosine hydroxylase 1 (hTH-1) under the negative control of the tetracycline-based gene regulatory system. Human neural progenitors infected with this vector produced large amounts of hTH-1. 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subjects | Adenoviridae - genetics Agriculture Animals Bioinformatics Biological and medical sciences Biomedical and Life Sciences Biomedical Engineering/Biotechnology Biomedicine Biotechnology Brain - cytology Brain - embryology Brain - enzymology Brain Tissue Transplantation Cell Transplantation Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Doxycycline - pharmacology Fetal Tissue Transplantation Fundamental and applied biological sciences. Psychology Gene Expression Regulation Gene therapy Gene Transfer Techniques Genetic Vectors Health. Pharmaceutical industry Humans Industrial applications and implications. Economical aspects Life Sciences Medical sciences Neurology Rats research-article Stem Cell Transplantation Stem Cells - virology Tyrosine 3-Monooxygenase - biosynthesis Tyrosine 3-Monooxygenase - genetics |
title | A single adenovirus vector mediates doxycycline-controlled expression of tyrosine hydroxylase in brain grafts of human neural progenitors |
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