Comparison of different gene-therapy methods to treat Leber hereditary optic neuropathy in a mouse model.
Comparison of different gene-therapy methods to treat Leber hereditary optic neuropathy in a mouse model.
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DOI：
10.3389/fnins.2023.1119724
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发表时间：
2023
影响因子：
4.3
通讯作者：
Yu, Hong
中科院分区：
文献类型：
--
作者：
Velmurugan, Sindhu;Chou, Tsung-Han;Eastwood, Jeremy D.;Porciatti, Vittorio;Liu, Yuan;Hauswirth, William W.;Guy, John;Yu, Hong
关键词：
Leber遗传性视神经病变(LHON)与所有由线粒体DNA突变引起的疾病一样，目前的治疗方法还不够充分。我们开发了两种针对这种疾病的基因治疗策略：线粒体靶向和异位表达，并在LHON小鼠模型中进行了比较。通过玻璃体内注射携带突变的人NADH脱氢酶4基因(hND4/m.11778G>；A)的线粒体靶向腺相关病毒(AAV)诱导视网膜神经节细胞(RGC)变性和轴突丢失，建立了LHON小鼠模型。然后，我们试图通过第二次玻璃体内注射线粒体靶向或异位表达的野生型人ND4来挽救这些小鼠。用连续模式视网膜电图(PERG)和透射电子显微镜观察RGCs及其轴突的挽救情况。与PERG波幅显著降低的非LHON对照组相比，这两种策略在15个月内都显著保持了PERG波幅。然而，线粒体靶向治疗的挽救效果比同种异体治疗更明显(p=0.0128)。死后分析表明，线粒体靶向的人类ND4更好地保存了人类LHON中优先丢失的小轴突。在临床前LHON小鼠模型中的这些结果表明，与异位AAV基因治疗相比，线粒体靶向AAV基因治疗在挽救LHON表型方面更有效。
Therapies for Leber hereditary optic neuropathy (LHON), in common with all disorders caused by mutated mitochondrial DNA, are inadequate. We have developed two gene therapy strategies for the disease: mitochondrial-targeted and allotopic expressed and compared them in a mouse model of LHON. A LHON mouse model was generated by intravitreal injection of a mitochondrialtargeted Adeno-associated virus (AAV) carrying mutant human NADH dehydrogenase 4 gene (hND4/m.11778G>A) to induce retinal ganglion cell (RGC) degeneration and axon loss, the hallmark of the human disease. We then attempted to rescue those mice using a second intravitreal injection of either mitochondrial-targeted or allotopic expressed wildtype human ND4. The rescue of RGCs and their axons were assessed using serial pattern electroretinogram (PERG) and transmission electron microscopy. Compared to non-rescued LHON controls where PERG amplitude was much reduced, both strategies significantly preserved PERG amplitude over 15 months. However, the rescue effect was more marked with mitochondrial-targeted therapy than with allotopic therapy (p = 0.0128). Post-mortem analysis showed that mitochondrial-targeted human ND4 better preserved small axons that are preferentially lost in human LHON. These results in a pre-clinical mouse model of LHON suggest that mitochondrially-targeted AAV gene therapy, compared to allotopic AAV gene therapy, is more efficient in rescuing the LHON phenotype.
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影响因子：
4.2
作者：
Lam, Byron L.;Feuer, William J.;Davis, Janet L.;Porciatti, Vittorio;Yu, Hong;Levy, Robert B.;Vanner, Elizabeth;Guy, John
通讯作者：
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影响因子：
13.7
作者：
Feuer WJ;Schiffman JC;Davis JL;Porciatti V;Gonzalez P;Koilkonda RD;Yuan H;Lalwani A;Lam BL;Guy J
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Guy J
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作者：
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通讯作者：
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影响因子：
4.4
作者：
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通讯作者：
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