Triple Transduction with Adeno-Associated Virus Vectors Expressing Tyrosine Hydroxylase, Aromatic-L-Amino-Acid Decarboxylase, and GTP Cyclohydrolase I for Gene Therapy of Parkinson's Disease
| Autor: | Shen, Y., Nagatsu, I., Urano, F., Suzuki, T., Ichinose, Hiroshi, Nagatsu, T., Monahan, J., Nakano, I., Ozawa, K., Muramatsu, S.-I., Ikeguchi, K., Fujimoto, K.-I., Fan, D.-S., Ogawa, M., Mizukami, H., Urabe, M., Kume, A. |
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| Rok vydání: | 2000 |
| Předmět: |
Male
medicine.medical_specialty Time Factors Tyrosine 3-Monooxygenase Dopamine GTP cyclohydrolase I Genetic Vectors Striatum Motor Activity Pharmacology medicine.disease_cause Cell Line Injections Transduction (genetics) Transformation Genetic Internal medicine Genetics medicine Animals Humans Transgenes Rats Wistar GTP Cyclohydrolase Oxidopamine Molecular Biology Adeno-associated virus Aromatic L-amino acid decarboxylase biology Tyrosine hydroxylase Gene Expression Profiling Gene Transfer Techniques Parkinson Disease Genetic Therapy Tetrahydrobiopterin Dependovirus Biopterin Corpus Striatum Rats Endocrinology Aromatic-L-Amino-Acid Decarboxylases biology.protein Molecular Medicine medicine.drug |
| Zdroj: | Human Gene Therapy. 11:1509-1519 |
| ISSN: | 1557-7422 1043-0342 |
| Popis: | Parkinson's disease (PD), a neurological disease suited to gene therapy, is biochemically characterized by a severe decrease in the dopamine content of the striatum. One current strategy for gene therapy of PD involves local production of dopamine in the striatum achieved by inducing the expression of enzymes involved in the biosynthetic pathway for dopamine. We previously showed that the coexpression of tyrosine hydroxylase (TH) and aromatic-L-amino-acid decarboxylase (AADC), using two separate adeno-associated virus (AAV) vectors, resulted in more effective dopamine production and more remarkable behavioral recovery in 6-hydroxydopamine-lesioned parkinsonian rats, compared with the expression of TH alone. Not only levels of TH and AADC but also levels of tetrahydrobiopterin (BH4), a cofactor of TH, and GTP cyclohydrolase I (GCH), a rate-limiting enzymes for BH4 biosynthesis, are reduced in parkinsonian striatum. In the present study, we investigated whether transduction with separate AAV vectors expressing TH, AADC, and GCH was effective for gene therapy of PD. In vitro experiments showed that triple transduction with AAV-TH, AAV-AADC, and AAV-GCH resulted in greater dopamine production than double transduction with AAV-TH and AAV-AADC in 293 cells. Furthermore, triple transduction enhanced BH4 and dopamine production in denervated striatum of parkinsonian rats and improved the rotational behavior of the rats more efficiently than did double transduction. Behavioral recovery persisted for at least 12 months after stereotaxic intrastriatal injection. These results suggest that GCH, in addition to TH and AADC, is important for effective gene therapy of PD. |
| Databáze: | OpenAIRE |
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