Friedreich ataxia (FRDA) is a serious hereditary neurodegenerative disease, mostly accompanied with hypertrophic cardiomyopathy, caused by the reduced expression of frataxin (FXN). However, there is still no effective treatment. Our previous studies have shown that SS-31, a mitochondrion-targeted peptide, is capable to upregulate the expression of FXN and improve the mitochondrial function in cells derived from FRDA patients. To further explore the potential of SS-31, we used the GAA expansion-based models, including Y47 and YG8R (Fxn KIKO) mice, primary neurons and macrophages from the mice and cells derived from FRDA patients. After once-daily intraperitoneal injection of 1 mg/kg SS-31 for 1 month, we observed the significant improvement of motor function. The vacuolation in dorsal root ganglia, lesions in dentate nuclei and the lost thickness of myelin sheath of spinal cord were all repaired after SS-31 treatment. In addition, the hypertrophic cardiomyocytes and disarrayed abnormal Purkinje cells were dramatically reduced. Interestingly, we found that SS-31 treatment upregulated FXN expression not only at the translational levels as observed in cell culture but also at mRNA levels in vivo. Consequently, mitochondrial morphology and function were greatly improved in all tested tissues. Importantly, our data provided additional evidence that the maintenance of the therapeutic benefits needed continuous drug administration. Taken together, our findings have demonstrated the effectiveness of SS-31 treatment through the upregulation of FXN in vivo and offer guidance of the potential usage in the clinical application for FRDA.

中文翻译：

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通过上调 frataxin 表达在 Friedreich 共济失调小鼠模型中的 SS-31 功效

弗里德赖希共济失调（FRDA）是一种严重的遗传性神经退行性疾病，多伴有肥厚型心肌病，由 frataxin（FXN）的表达降低引起。但是，仍然没有有效的治疗方法。我们之前的研究表明，SS-31 是一种线粒体靶向肽，能够上调 FXN 的表达并改善来自 FRDA 患者的细胞的线粒体功能。为了进一步探索 SS-31 的潜力，我们使用了基于 GAA 扩展的模型，包括 Y47 和 YG8R (Fxn KIKO) 小鼠、来自小鼠的原代神经元和巨噬细胞以及来自 FRDA 患者的细胞。每天一次腹腔注射 1 mg/kg SS-31 1 个月后，我们观察到运动功能显着改善。背根神经节的空泡化，SS-31治疗后齿状核损伤和脊髓髓鞘厚度损失均得到修复。此外，肥大的心肌细胞和杂乱无章的异常浦肯野细胞显着减少。有趣的是，我们发现 SS-31 处理不仅在细胞培养中观察到的翻译水平上调 FXN 表达，而且在体内 mRNA 水平上也上调了 FXN 表达。因此，所有测试组织中的线粒体形态和功能都得到了极大的改善。重要的是，我们的数据提供了额外的证据，表明维持治疗益处需要持续给药。总之，我们的研究结果通过体内 FXN 的上调证明了 SS-31 治疗的有效性，并为 FRDA 在临床应用中的潜在用途提供了指导。