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• W4328001158 abstract "Gene transfer of tyrosine hydroxylase (TH) in animal models of Parkinson’s disease (PD), using either genetically modified cells or recombinant virus vectors, has produced partial restoration of behavioral and biochemical deficits. The limited success of this approach may be related to the availability of the cofactor, tetrahydrobiopterin (BH 4 ), because neither the dopamine-depleted striatum nor the cells used for gene transfer possess a sufficient amount of BH 4 to support TH activity. To determine the role of BH 4 in gene therapy, fibroblast cells transduced with the gene for TH were additionally modified with the gene for GTP cyclohydrolase I, an enzyme critical for BH 4 synthesis. In contrast to cells transduced with only TH, doubly transduced fibroblasts spontaneously produced both BH 4 and 3,4-dihydroxy- l -phenylalanine. To examine further the importance of GTP cyclohydrolase I in gene therapy for PD, in vivo microdialysis was used to assess the biochemical changes in the dopamine-denervated striatum containing grafts of genetically modified fibroblasts. Only denervated striata grafted with fibroblasts possessing both TH and GTP cyclohydrolase I genes displayed biochemical restoration. However, no significant differences from controls were observed in apomorphine-induced rotation. This is partly attributable to a limited duration of gene expression in vivo . These differences between fibroblasts transduced with TH alone and those additionally modified with the GTP cyclohydrolase I gene indicate that BH 4 is critical for biochemical restoration in a rat model of PD and that GTP cyclohydrolase I is sufficient for production of BH 4 ." @default.
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• W4328001158 date "1996-07-15" @default.
• W4328001158 modified "2023-10-18" @default.
• W4328001158 title "Double Transduction with GTP Cyclohydrolase I and Tyrosine Hydroxylase Is Necessary for Spontaneous Synthesis ofl-DOPA by Primary Fibroblasts" @default.
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• W4328001158 doi "https://doi.org/10.1523/jneurosci.16-14-04449.1996" @default.
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