Successful amelioration of mitochondrial optic neuropathy using the yeast NDI1 gene in a rat animal model.
Successful amelioration of mitochondrial optic neuropathy using the yeast NDI1 gene in a rat animal model.
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DOI：
10.1371/journal.pone.0011472
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发表时间：
2010-07-08
期刊：
影响因子：
3.7
通讯作者：
Yagi T
中科院分区：
文献类型：
--
作者：
Marella M;Seo BB;Thomas BB;Matsuno-Yagi A;Yagi T
Leber遗传性视神经病变(LHON)是一种母系遗传性疾病，线粒体DNA点突变导致年轻人丧失视力。到目前为止，报道的大多数突变发生在线粒体NADH-Q氧化还原酶亚单位的编码基因内，复合体I。建立LHON的动物模型将有助于阐明该病的发病机制，并可用于可能的治疗策略的开发。我们建立了一种将鱼藤酮微球注射到大鼠上丘视层的大鼠模型。这些动物表现出LHON最常见的特征。注射鱼藤酮后2周内视力下降，对视网膜神经节细胞无明显影响。晚期视网膜神经节细胞死亡。利用我们的大鼠模型，我们研究了酵母替代NADH脱氢酶Ndi1的作用。我们通过将NDI1基因转移到上丘的光层，实现了NDI1蛋白在视网膜神经节细胞和轴突的所有区域的线粒体中的高效表达。值得注意的是，即使在大鼠的视力严重受损后，用NDI1基因治疗动物也能使视力完全恢复到正常水平。接受空载体或GFP基因的对照组没有任何效果。本研究成功地在大鼠中表现出LHON样症状，并证明了NDI1基因治疗线粒体视神经病变的潜力。我们的结果表明，在疾病症状出现后，基因治疗是成功应用的机会之窗。
Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder with point mutations in mitochondrial DNA which result in loss of vision in young adults. The majority of mutations reported to date are within the genes encoding the subunits of the mitochondrial NADH-quinone oxidoreductase, complex I. Establishment of animal models of LHON should help elucidate mechanism of the disease and could be utilized for possible development of therapeutic strategies. We established a rat model which involves injection of rotenone-loaded microspheres into the optic layer of the rat superior colliculus. The animals exhibited the most common features of LHON. Visual loss was observed within 2 weeks of rotenone administration with no apparent effect on retinal ganglion cells. Death of retinal ganglion cells occurred at a later stage. Using our rat model, we investigated the effect of the yeast alternative NADH dehydrogenase, Ndi1. We were able to achieve efficient expression of the Ndi1 protein in the mitochondria of all regions of retinal ganglion cells and axons by delivering the NDI1 gene into the optical layer of the superior colliculus. Remarkably, even after the vision of the rats was severely impaired, treatment of the animals with the NDI1 gene led to a complete restoration of the vision to the normal level. Control groups that received either empty vector or the GFP gene had no effects. The present study reports successful manifestation of LHON-like symptoms in rats and demonstrates the potential of the NDI1 gene therapy on mitochondrial optic neuropathies. Our results indicate a window of opportunity for the gene therapy to be applied successfully after the onset of the disease symptoms.
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影响因子：
4.2
作者：
Cideciyan, Artur V.;Hauswirth, William W.;Jacobson, Samuel G.
通讯作者：
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10.1007/s004170050220
发表时间：
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