Gene transfer for neuroprotection in animal models of Parkinson's disease and amyotrophic lateral sclerosis

被引:17
作者
Bohn, MC
Connor, B
Kozlowski, DA
Mohajeri, MH
机构
[1] Northwestern Univ, Sch Med, Dept Pediat, Childrens Mem Inst Educ & Res, Chicago, IL 60614 USA
[2] Univ Zurich, Dept Psychiat Res, Zurich, Switzerland
来源
NEURAL TRANSPLANTATION IN NEURODEGENERATIVE DISEASE: CURRENT STATUS AND NEW DIRECTIONS | 2000年 / 231卷
关键词
D O I
10.1002/0470870834.ch5
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for motoneurons (MN) and dopaminergic (DA) neurons, neurons which selectively die in amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). GDNF gene delivery has been studied in rodent models of ALS and PD. In a mouse model of ALS, implantation of myoblasts retrovirally transduced with GDNF into hindlimb muscles at 6 weeks of age, i.e. prior to the onset of disease symptoms, increased the number of large MNs that maintained projections to treated muscles at 18 weeks of age. GDNF-treated mice also performed better on tests of motor function and had a delayed onset of disease. In a progressive degeneration rat model of PD, effects of in vivo GDNF gene therapy using an adenoviral vector (AdGDNF) were studied in young and aged rats, AdGDNF protected DA neurons against the neurotoxin, 6-hydroxydopamine (6-OHDA), and was effective whether injected either before or after 6-OHDA damage had commenced. However, if AdGDNF was injected prior to 6-OHDA, it was most effective in protecting against DA-dependent changes in the bra-in when injected near the terminals of the DA neurons. In contrast, if 6-OHDA damage had already commenced, AdGDNF was most effective if injected near the DA soma. These studies suggest that GDNF gene delivery into specific sites in the CNS or into muscle where MNS have access to secreted GDNF may slow the progression of PD and ALS, respectively. Neurotrophic factor gene therapy offers novel interventions not only for PD and ALS, but also other neurodegenerative diseases and injuries to the nervous system.
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页码:70 / 89
页数:20
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