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首页> 外文期刊>Nature >Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington's disease
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Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington's disease

机译：产生神经营养因子CNTF的包囊细胞对亨廷顿舞蹈病模型的保护作用

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摘要

Huntington's disease is a genetic disorder that results from degeneration of striatal neurons, particularly those containing GABA (gamma-aminobutyric acid). There is no effective treatment for preventing or slowing this neuronal degeneration. Ciliary neurotrophic factor (CNTF) is a trophic factor for striatal neurons and therefore a potential therapeutic agent for Huntington's disease. Here we evaluate CNTF as a neuroprotective agent in a nonhuman primate model of Huntington's disease. We gave cynomolgus monkeys intrastriatal implants of polymer-encapsulated baby hamster kidney fibroblasts that had been genetically modified to secrete human CNTF. One week later, monkeys received unilateral injections of quinolinic acid into the previously implanted striatum to reproduce the neuropathology seen in Huntington's disease. Human CNTF was found to exert a neuroprotective effect on several populations of striatal cells, including GABAergic, cholinergic and diaphorase-positive neurons which were all destined to die following administration of quinolinic acid. Human CNTF also prevented the retrograde atrophy of layer V neurons in motor cortex and exerted a significant protective effect on the GABAergic innervation of the two important target fields of the striatal output neurons (the globus pallidus and pars reticulata of the substantia nigra). Our results show that human CNTF has a trophic influence on degenerating striatal neurons as well as on critical non-striatal regions such as the cerebral cortex, supporting the idea that human CNTF may help to prevent the degeneration of vulnerable striatal populations and cortical-striatal basal ganglia circuits in Huntington's disease.
机译：亨廷顿舞蹈病是一种遗传疾病，是由纹状体神经元（尤其是含有GABA（γ-氨基丁酸）的神经元）退化引起的。没有预防或减缓这种神经元变性的有效疗法。睫状神经营养因子（CNTF）是纹状体神经元的营养因子，因此是亨廷顿氏病的潜在治疗剂。在这里，我们评估CNTF作为亨廷顿氏病非人类灵长类动物模型中的神经保护剂。我们给食蟹猕猴进行了基因修饰以分泌人CNTF的聚合物封装的小仓鼠肾脏成纤维细胞的纹状体植入物。一周后，猴子向先前植入的纹状体单方面注射喹啉酸，以重现亨廷顿舞蹈病中的神经病理学。发现人类CNTF对纹状体细胞的几种种群具有神经保护作用，包括GABA能，胆碱能和心肌黄递酶阳性的神经元，这些神经元注定要在服用喹啉酸后死亡。人CNTF还可以防止运动皮质V层神经元的逆行萎缩，并对纹状体输出神经元的两个重要靶区域（苍白球和黑质的网状面）的GABA能神经支配具有显着的保护作用。我们的结果表明，人类CNTF对退化的纹状体神经元以及关键非纹状体区域（例如大脑皮层）具有营养作用，支持了人类CNTF可以帮助防止脆弱的纹状体人群和皮质-纹状体基底变性的想法神经节回路在亨廷顿氏病中。

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