EJHG：新方法或为治疗遗传性视神经病变提供思路

细胞中的基因疗法应用于线粒体。

(Image: Ron Boardman/Getty Images)

在细胞中，线粒体就像小型发电机一样为机体提供能量，但是当线粒体功能发生错误，就会引发一系列疾病。产生疾病的根源就在于线粒体中的DNA的突变，线粒体中的DNA和细胞核中的DNA是不同的。由于线粒体异常所导致的遗传性视神经病变（LHON）可以引发成年人丧失视力。

在LHON患者中，线粒体中DNA部分编码的蛋白质Complex-I的功能会出现故障，这种异常会导致眼睛后部的视网膜神经节细胞死亡。运用基因疗法对线粒体DNA进行低频干扰目前正在研发中，因为这种疗法可以干扰许多细胞中线粒体DNA发挥功能。如今来自爱尔兰的研究者Jane Farrar和其同事阐述了这一领域的工作，他们以细胞核为靶标，让其产生Complex-I类型蛋白质，这种蛋白质可以进入细胞的线粒体中。尽管研究者的方法并不是一种全新的方法，但是这项研究可以轻松应用于眼睛疾病的治疗中。

研究者通过使用药物抑制Complex-I，构建了LHON症状的小鼠模型，通过在模型中进行眼部注射，随后研究者用病毒载体将酿酒酵母的基因运输至啮齿动物视网膜神经节细胞的细胞核中，基因NDI1可以编码类似哺乳动物蛋白Complex-I。而且该基因可以在细胞核内被开启，并且该基因编码的蛋白质可以补充因为Complex-I异常所产生的效应。

Farrar表示，理论上，无论什么突变引起原始的缺陷，这种系统都可以补充Complex-I蛋白的不足。这项研究同时也为开发LHON病人的治疗方法提供了一些建议。相关研究成果刊登在了国际著名杂志European Journal of Human Genetics上。

编译自：Mitochondrial disorder treated by targeting nucleus

编译者：T.Shen

doi:10.1038/ejhg.2012.112
PMC:
PMID:

Intravitreal delivery of AAV-NDI1 provides functional benefit in a murine model of Leber hereditary optic neuropathy

Naomi Chadderton1, Arpad Palfi1,4, Sophia Millington-Ward1,4, Oliverio Gobbo2, Nora Overlack3, Matthew Carrigan1, Mary O'Reilly1, Matthew Campbell1, Carsten Ehrhardt2, Uwe Wolfrum3, Peter Humphries1, Paul F Kenna1 and G Jane Farrar1

Leber hereditary optic neuropathy (LHON) is a mitochondrially inherited form of visual dysfunction caused by mutations in several genes encoding subunits of the mitochondrial respiratory NADH-ubiquinone oxidoreductase complex (complex I). Development of gene therapies for LHON has been impeded by genetic heterogeneity and the need to deliver therapies to the mitochondria of retinal ganglion cells (RGCs), the cells primarily affected in LHON. The therapy under development entails intraocular injection of a nuclear yeast gene NADH-quinone oxidoreductase (NDI1) that encodes a single subunit complex I equivalent and as such is mutation independent. NDI1 is imported into mitochondria due to an endogenous mitochondrial localisation signal. Intravitreal injection represents a clinically relevant route of delivery to RGCs not previously used for NDI1. In this study, recombinant adenoassociated virus (AAV) serotype 2 expressing NDI1 (AAV-NDI1) was shown to protect RGCs in a rotenone-induced murine model of LHON. AAV-NDI1 significantly reduced RGC death by 1.5-fold and optic nerve atrophy by 1.4-fold. This led to a significant preservation of retinal function as assessed by manganese enhanced magnetic resonance imaging and optokinetic responses. Intraocular injection of AAV-NDI1 overcomes many barriers previously associated with developing therapies for LHON and holds great therapeutic promise for a mitochondrial disorder for which there are no effective therapies.