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- W2070062163 abstract "Parkinson's disease (PD) is well|[ndash]|defined brain disorder in which slow degeneration of nigrostriatal dopaminergic neurons in the pars compacta of the substantia nigra, results in neurological signs. Since dopamine cannot cross the blood|[ndash]|brain barrier (BBB), the current treatment for PD is a replacement strategy in which the dopamine precursor, L|[ndash]|dopa that crosses the BBB, is given orally several times a day. However, L|[ndash]|dopa efficacy decreases as the neurodegeneration of the dopaminergic innervation of the striatum progresses. Thus, patients are obliged to take higher doses of the drug, a process that leads to considerable fluctuations in L|[ndash]|dopa levels and a gradual decline of the therapeutic benefits. We have demonstrated that the delivery of AADC enzyme to the striatum of parkinsonian monkeys by means of adeno|[ndash]|associated viral vector|[ndash]|mediated AADC gene transfer (AAV-AADC) increases the efficiency of L|[ndash]|dopa conversion to dopamine. This approach improved motor behavioral of the parkinsonian monkeys in response to low otherwise sub|[ndash]|clinical doses of L|[ndash]|dopa. In the present study we used immunohistochemistry, stereology, quantitative PCR and positron emission tomography (PET) to quantify and compare the efficiency of gene transfer and distribution of AAV|[ndash]|AADC, 8 weeks, 3 years and 5 years after gene transfer. Two cohorts of hemi|[ndash]|parkinsonian monkeys received the same dose of AAV|[ndash]|AADC into the MPTP|[ndash]|lesioned hemisphere. Each monkey was infused by convection|[ndash]|enhanced delivery with AAV-AADC (2 |[times]| 1012 vg/ml; 30 |[mu]|l/site) at a total of 6 sites: 2 in the caudate and 4 in the putamen. We used immunochemical staining with anti|[ndash]|AADC antibodies to measure expression of AADC at 8 weeks and 3 years after gene transfer, and related this expression to the number of copies of vector DNA at each time point by quantitative PCR analysis. We demonstrated that gene transfer of AAV|[ndash]|AADC was strong and widespread at both 8 weeks and 3 years post|[ndash]|surgery. Interestingly, we observed a significant increase in the number of positive neurons in the striatum at 3 years compared to 8 weeks, suggesting perhaps that further transduction takes place many weeks after the gene transfer surgery. Furthermore, in a separate cohort of monkeys treated identically to those used for tissue analysis, PET scanning with the AADC|[ndash]|specific tracer FMT demonstrated continued stable expression for more than 5 years. This is to our knowledge the longest documented persistence of AAV|[ndash]|mediated gene transfer. In conclusion, we have shown that (i) AAV|[ndash]|AADC drives widespread and persistent expression of AADC in the striatum, and (ii) distribution of AADC immunoreactive cells is surprisingly more widespread and homogeneous 3 years after gene transfer." @default.
- W2070062163 created "2016-06-24" @default.
- W2070062163 date "2005-05-01" @default.
- W2070062163 modified "2023-09-26" @default.
- W2070062163 title "942. Evaluation of Short (8 Weeks) and Long-Term (3 and 5 Years) Gene Transfer Following Brain Delivery of AAV-AADC Vector in Parkinsonian Monkeys" @default.
- W2070062163 doi "https://doi.org/10.1016/j.ymthe.2005.07.485" @default.
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