Therapeutic Effects of the Mitochondrial ROS-redox Modulator KH176 in a Mammalian Model of Leigh Disease

Overview

Journal Sci Rep

Specialty Science

Date 2017 Sep 17

PMID 28916769

Citations 21

Authors

Ria de Haas

Devashish Das

Alejandro Garanto

Herma G Renkema

Rick Greupink

Petra Van Den Broek

Jeanne Pertijs

Rob W J Collin

Peter Willems

Julien Beyrath

Arend Heerschap

Frans G Russel

Jan A Smeitink

Affiliations

Soon will be listed here.

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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