Gene therapy now provides a novel approach for treating inherited monogenetic disorders, including nuclear gene mutations associated with mitochondrial diseases. In this study, we have utilized a mouse model carrying a p.Arg389Gln mutation of the mitochondrial Ferredoxin Reductase gene (Fdxr) and treated them with neurotropic AAV-PHP.B vector loaded with the mouse Fdxr cDNA sequence. We then used immunofluorescence staining and western blot to test the transduction efficiency of this vector. Toluidine blue staining and electronic microscopy were also utilized to assess the morphology of optic and sciatic nerves, and the mitochondrial respiratory chain activity was determined as well. The AAV vector effectively transduced in the central nervous system and peripheral organs, and AAV-Fdxr treatment reversed almost all the symptoms of the mutants (Fdxr^R389Q/R389Q). This therapy also improved the electronic conductivity of the sciatic nerves, prevented optic atrophy, improved mobility, and restored mitochondrial complex function. Most notably, the sensory neuropathy, neurodegeneration, and chronic neuroinflammation in the brain were alleviated. Overall, we present the first demonstration of a potential definitive treatment that significantly improves optic and sciatic nerve atrophy, sensory neuropathy, and mitochondrial dysfunction in FDXR-related mitochondriopathy. Our study provides substantial support for the translation of AAV-based Fdxr gene therapy into clinical applications.

基因治疗现在提供了一种治疗遗传性单基因疾病的新方法，包括与线粒体疾病相关的核基因突变。在这项研究中，我们利用了携带线粒体铁氧还蛋白还原酶基因（Fdxr）p.Arg389Gln突变的小鼠模型，并用载有小鼠Fdxr的神经质AAV-PHP.B载体对其进行了处理。cDNA序列。然后，我们使用免疫荧光染色和蛋白质印迹来测试该载体的转导效率。甲苯胺蓝染色和电子显微镜还用于评估视神经和坐骨神经的形态，并确定线粒体呼吸链活性。AAV载体可在中枢神经系统和周围器官中有效转导，并且AAV- Fdxr处理可逆转几乎所有突变体的症状（Fdxr ^{R389Q / R389Q} ）。该疗法还改善了坐骨神经的电子传导性，防止了视神经萎缩，改善了活动能力，并恢复了线粒体复合功能。最值得注意的是，大脑的感觉神经病，神经变性和慢性神经炎症得到缓解。总体而言，我们首次展示了潜在的最终治疗方法，该方法可显着改善FDXR相关性线粒体病中的视神经和坐骨神经萎缩，感觉神经病和线粒体功能障碍。我们的研究为将基于AAV的Fdxr基因治疗转化为临床应用提供了实质性支持。