Gene transfer for neuroprotection in animal models of Parkinson's disease and amyotrophic lateral sclerosis
Gene transfer for neuroprotection in animal models of Parkinson's disease and amyotrophic lateral sclerosis
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DOI：
10.1002/0470870834.ch5
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发表时间：
2000-01-01
期刊：
影响因子：
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通讯作者：
Mohajeri, MH
中科院分区：
文献类型：
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作者：
Bohn, MC;Connor, B;Mohajeri, MH
胶质细胞源性神经营养因子（GDNF）是运动神经元（MN）和多巴胺能（DA）神经元的有效存活因子，运动神经元和多巴胺能神经元在肌萎缩侧索硬化（ALS）和帕金森病（PD）中选择性死亡。已在ALS和PD的啮齿动物模型中研究了GDNF基因递送。在ALS的小鼠模型中，在6周龄时，即在疾病症状发作之前，将GDNF逆转录病毒转导的成肌细胞植入后肢肌肉中，增加了在18周龄时保持向治疗肌肉投射的大MN的数量。GDNF治疗的小鼠在运动功能测试中也表现得更好，并且延迟了疾病的发作。在PD进行性变性大鼠模型中，研究了使用腺病毒载体（AdGDNF）的体内GDNF基因治疗在年轻和老年大鼠中的作用，AdGDNF保护DA神经元免受神经毒素6-羟基多巴胺（6-OHDA）的影响，并且无论在6-OHDA损伤开始之前或之后注射都是有效的。然而，如果在6-OHDA之前注射AdGDNF，则当在DA神经元的末梢附近注射时，它在保护bra-in免受DA依赖性变化方面最有效。相比之下，如果6-OHDA损伤已经开始，AdGDNF是最有效的，如果附近的DA索马注射。这些研究表明，将GDNF基因递送到CNS中的特定位点或MNS可以获得分泌的GDNF的肌肉中，可以分别减缓PD和ALS的进展。神经营养因子基因治疗不仅为PD和ALS提供了新的干预措施，而且还为其他神经退行性疾病和神经系统损伤提供了新的干预措施。
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.