de Haas Ria, Das Devashish, Garanto Alejandro, Renkema Herma G, Greupink Rick, van den Broek Petra, Pertijs Jeanne, Collin Rob W J, Willems Peter, Beyrath Julien, Heerschap Arend, Russel Frans G, Smeitink Jan A
Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Pharmacology and Toxicology, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Sci Rep. 2017 Sep 15;7(1):11733. doi: 10.1038/s41598-017-09417-5.
Leigh Disease is a progressive neurometabolic disorder for which a clinical effective treatment is currently still lacking. Here, we report on the therapeutic efficacy of KH176, a new chemical entity derivative of Trolox, in Ndufs4 mice, a mammalian model for Leigh Disease. Using in vivo brain diffusion tensor imaging, we show a loss of brain microstructural coherence in Ndufs4 mice in the cerebral cortex, external capsule and cerebral peduncle. These findings are in line with the white matter diffusivity changes described in mitochondrial disease patients. Long-term KH176 treatment retained brain microstructural coherence in the external capsule in Ndufs4 mice and normalized the increased lipid peroxidation in this area and the cerebral cortex. Furthermore, KH176 treatment was able to significantly improve rotarod and gait performance and reduced the degeneration of retinal ganglion cells in Ndufs4 mice. These in vivo findings show that further development of KH176 as a potential treatment for mitochondrial disorders is worthwhile to pursue. Clinical trial studies to explore the potency, safety and efficacy of KH176 are ongoing.
Leigh病是一种进行性神经代谢障碍疾病，目前仍缺乏临床有效的治疗方法。在此，我们报告了一种新的化学实体——Trolox衍生物KH176，在Ndufs4小鼠（一种Leigh病的哺乳动物模型）中的治疗效果。通过体内脑扩散张量成像，我们发现Ndufs4小鼠的大脑皮层、外囊和脑桥中脑微结构连贯性丧失。这些发现与线粒体疾病患者中描述的白质扩散率变化一致。长期使用KH176治疗可使Ndufs4小鼠外囊中的脑微结构连贯性得以保留，并使该区域和大脑皮层中增加的脂质过氧化恢复正常。此外，KH176治疗能够显著改善Ndufs4小鼠的转棒试验和步态表现，并减少视网膜神经节细胞的退化。这些体内研究结果表明，将KH176进一步开发为线粒体疾病的潜在治疗方法是值得探索的。目前正在进行临床试验研究，以探究KH176的效力、安全性和疗效。
