Long-term doxycycline-controlled expression of human tyrosine hydroxylase after direct adenovirus-mediated gene transfer to a rat model of Parkinson’s disease
Identifieur interne : 003C49 ( Main/Exploration ); précédent : 003C48; suivant : 003C50Long-term doxycycline-controlled expression of human tyrosine hydroxylase after direct adenovirus-mediated gene transfer to a rat model of Parkinson’s disease
Auteurs : Olga Corti [France] ; Amelia Sánchez-Capelo [France] ; Philippe Colin [France] ; Naïma Hanoun [France] ; Michel Hamon [France] ; Jacques Mallet [France]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 1999.
English descriptors
- KwdEn :
- Adenoviridae (genetics), Animals, Anti-Bacterial Agents (pharmacology), Antiparkinson Agents (pharmacology), Apomorphine (pharmacology), Corpus Striatum (metabolism), Disease Models, Animal, Dopamine (metabolism), Doxycycline (pharmacology), Female, Gene Expression Regulation, Gene Transfer Techniques, Humans, Immunohistochemistry, Oxidopamine, Parkinson Disease (genetics), Parkinson Disease (therapy), Rats, Rats, Sprague-Dawley, Time Factors, Tyrosine 3-Monooxygenase (biosynthesis), Tyrosine 3-Monooxygenase (genetics), Tyrosine 3-Monooxygenase (metabolism).
- MESH :
- chemical , biosynthesis : Tyrosine 3-Monooxygenase.
- chemical , genetics : Tyrosine 3-Monooxygenase.
- chemical , metabolism : Dopamine, Tyrosine 3-Monooxygenase.
- chemical , pharmacology : Anti-Bacterial Agents, Antiparkinson Agents, Apomorphine, Doxycycline.
- genetics : Adenoviridae, Parkinson Disease.
- metabolism : Corpus Striatum.
- therapy : Parkinson Disease.
- Animals, Disease Models, Animal, Female, Gene Expression Regulation, Gene Transfer Techniques, Humans, Immunohistochemistry, Oxidopamine, Rats, Rats, Sprague-Dawley, Time Factors.
Abstract
Developments of technologies for delivery of foreign genes to the central nervous system are opening the field to promising treatments for human neurodegenerative diseases. Gene delivery vectors need to fulfill several criteria of efficacy and safety before being applied to humans. The ability to drive expression of a therapeutic gene in an adequate number of cells, to maintain long-term expression, and to allow exogenous control over the transgene product are essential requirements for clinical application. We describe the use of an adenovirus vector encoding human tyrosine hydroxylase (TH) 1 under the negative control of the tetracycline-sensitive gene regulatory system for direct injection into the dopamine-depleted striatum of a rat model of Parkinson’s disease. This vector mediated synthesis of TH in numerous striatal cells and transgene expression was observed in a large proportion of them for at least 17 weeks. Furthermore, doxycyline, a tetracycline analog, allowed efficient and reversible control of transgene expression. Thus, the insertion of a tetracycline-sensitive regulatory cassette into a single adenovirus vector provides a promising system for the development of successful and safe therapies for human neurological diseases. Our results also confirm that future effective gene replacement approaches to Parkinson’s disease will have to consider the concomitant transfer of TH and GTP-cyclohydrolase transgenes because the synthesis of the TH cofactor tetrahydrobiopterin may be crucial for restoration of the dopaminergic deficit.
Url:
PubMed: 10518586
PubMed Central: 18422
Affiliations:
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Le document en format XML
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<front><div type="abstract" xml:lang="en"><p>Developments of technologies for delivery of foreign genes to the central nervous system are opening the field to promising treatments for human neurodegenerative diseases. Gene delivery vectors need to fulfill several criteria of efficacy and safety before being applied to humans. The ability to drive expression of a therapeutic gene in an adequate number of cells, to maintain long-term expression, and to allow exogenous control over the transgene product are essential requirements for clinical application. We describe the use of an adenovirus vector encoding human tyrosine hydroxylase (TH) 1 under the negative control of the tetracycline-sensitive gene regulatory system for direct injection into the dopamine-depleted striatum of a rat model of Parkinson’s disease. This vector mediated synthesis of TH in numerous striatal cells and transgene expression was observed in a large proportion of them for at least 17 weeks. Furthermore, doxycyline, a tetracycline analog, allowed efficient and reversible control of transgene expression. Thus, the insertion of a tetracycline-sensitive regulatory cassette into a single adenovirus vector provides a promising system for the development of successful and safe therapies for human neurological diseases. Our results also confirm that future effective gene replacement approaches to Parkinson’s disease will have to consider the concomitant transfer of TH and GTP-cyclohydrolase transgenes because the synthesis of the TH cofactor tetrahydrobiopterin may be crucial for restoration of the dopaminergic deficit.</p>
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