2. Academic Validation
  3. Therapeutic effects of the mitochondrial ROS-redox modulator KH176 in a mammalian model of Leigh Disease

Therapeutic effects of the mitochondrial ROS-redox modulator KH176 in a mammalian model of Leigh Disease

  • Sci Rep. 2017 Sep 15;7(1):11733. doi: 10.1038/s41598-017-09417-5.
Ria de Haas 1 2,  Devashish Das 3,  Alejandro Garanto 4,  Herma G Renkema 1,  Rick Greupink 2,  Petra van den Broek 2,  Jeanne Pertijs 2,  Rob W J Collin 4,  Peter Willems 5,  Julien Beyrath 6,  Arend Heerschap 3,  Frans G Russel 2,  Jan A Smeitink 7 8
Affiliations

Affiliations

  • 1 Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 2 Department of Pharmacology and Toxicology, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 3 Department of Radiology and Nuclear Medicine, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 4 Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 5 Department of Biochemistry, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 6 Khondrion BV, Nijmegen, The Netherlands.
  • 7 Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. jan.smeitink@radboudumc.nl.
  • 8 Khondrion BV, Nijmegen, The Netherlands. jan.smeitink@radboudumc.nl.
PMID: 28916769 DOI: 10.1038/s41598-017-09417-5
Abstract

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.

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