Nonviral glial cell-derived neurotrophic factor gene transfer enhances survival of cultured dopaminergic neurons and improves their function after transplantation in a rat model of Parkinson's disease

被引:20
作者
Bauer, M
Meyer, M
Grimm, L
Meitinger, T
Zimmer, J
Gasser, T
Ueffing, M
Widmer, HR
机构
[1] GSF Munich, Natl Res Ctr Environm & Hlth, Inst Clin Mol Biol, D-81377 Munich, Germany
[2] Univ Munich, Klinikum Grosshadern, Dept Neurol, D-81377 Munich, Germany
[3] USD Odense Univ, Dept Anat & Neurobiol, DK-5000 Odense C, Denmark
[4] Tech Univ Munich, Inst Human Genet, Munich, Germany
[5] GSF Munich, Natl Res Ctr, D-81377 Munich, Germany
[6] Univ Bern, Inselspital, Dept Neurosurg, CH-3010 Bern, Switzerland
关键词
D O I
10.1089/10430340050083261
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Transplantation of dopaminergic fetal mesencephalic tissue into the striatum is currently being developed for treatment of patients with advanced Parkinson's disease. Ethical concerns regarding the use of human fetal tissue, and the limited availability as well as poor survival and differentiation of dopaminergic neurons after transplantation have reduced the extent and outcome of this approach so far. With the purpose of finding means to increase the yield of dopaminergic neurons in transplants, and to reduce the amount of fetal tissue needed for each transplanted patient, we transfected rat fetal ventral mesencephalic (VM) tissue grown as organotypic free-floating roller tube (FFRT) cultures with a vector encoding human glial cell-derived neurotrophic factor (hGDNF), For transfer of an episomal expression vector (pRep7-GDNF8) a nonviral, nonliposomal cationic transfection technique was applied and optimized. Recombinant hGDNF expression resulted in a higher number of TH-positive neurons in the cultures as measured 6 days after transfection, Ventral mesencephalic cultures expressing hGDNF were then grafted into the striatum of unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. Grafting of genetically modified VM cultures resulted in earlier functional recovery compared with grafting nontransfected cultures. We conclude that organotypic free-floating roller tube cultures can be successfully transfected to produce hGDNF with effects on TH-expressing neurons in vitro and functional effects after grafting in a rat Parkinson's disease model.
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页码:1529 / 1541
页数:13
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