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

Haas, Ria de; Das, Devashish; Garanto, Alejandro; Renkema, G. Herma; Greupink, Rick; Broek, Petra van den; Pertijs, Jeanne; Collin, Rob W.J.; Willems, Peter H.G.M.; Heerschap, Arend; Rüssel, Frans G. M.; Smeitink, Jan A.M.

doi:10.1038/s41598-017-09417-5

Cited by 36 publications

(30 citation statements)

References 70 publications

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“…In 18 evaluable patients, this phase IIA trial revealed that 100‐mg KH176 b.i.d. was well tolerated, showed a favorable safety profile, and had a pharmacokinetic profile comparable with that of healthy male volunteers in the previous phase I trial …”

Section: Discussionmentioning

confidence: 70%

“…Others demonstrated that these patients had an abnormal gait pattern, as quantified by gait analysis . For this reason, and the observation that gait improved during KH176 treatment in a mitochondrial disease mouse model, gait was chosen as a primary end point . This 28‐day phase IIA study showed no improvement in gait parameters.…”

Section: Discussionmentioning

confidence: 99%

“…17 Furthermore, KH176 treatment was able to significantly improve rotarod and gait performance and reduced the degeneration of retinal ganglion cells in Ndufs4 (−/−) mice. 17 A phase I clinical trial in healthy volunteers deemed that KH176 is well tolerated up to single doses of 800 mg and multiple doses of 400 mg b.i.d. and had a pharmacokinetic profile supportive of a twice daily (b.i.d.)…”

mentioning

confidence: 92%

“…KH176 is considered to be a prodrug being active similar to its metabolite KH176 m. Preclinical studies in patient‐derived fibroblasts with a wide variability of genetic backgrounds showed that KH176 had a protective effect against redox perturbation in cells. In complex I deficient knockout mice ( Ndufs4 −/− ), KH176 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 .…”

mentioning

confidence: 99%

“…In complex I deficient knockout mice ( Ndufs4 −/− ), KH176 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 . A phase I clinical trial in healthy volunteers deemed that KH176 is well tolerated up to single doses of 800 mg and multiple doses of 400 mg b.i.d.…”

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confidence: 99%

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The KHENERGY Study: Safety and Efficacy of KH176 in Mitochondrial m.3243A>G Spectrum Disorders

Janssen

Koene

Laat

et al. 2018

Clin Pharma and Therapeutics

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KH176 is a potent intracellular reduction-oxidation-modulating compound developed to treat mitochondrial disease. We studied tolerability, safety, pharmacokinetics, pharmacodynamics, and efficacy of twice daily oral 100 mg KH176 for 28 days in a double-blind, randomized, placebo-controlled, two-way crossover phase IIA study in 18 adult m.3243A>G patients without cardiovascular involvement. Efficacy parameters included clinical and functional outcome measures and biomarkers. The trial was registered within ClinicalTrials.gov (NCT02909400), the European Clinical Trials Database (2016-001696-79), and ISRCTN (43372293) (The KHENERGY study). Twice daily oral 100 mg KH176 was well tolerated and appeared safe. No serious treatment-emergent adverse events were reported. No significant improvements in gait parameters or other outcome measures were obtained, except for a positive effect on alertness and mood, although a coincidence due to multiplicity cannot be ignored. The results of the study provide first data on safety and efficacy of KH176 in patients with mitochondrial disease and will be instrumental in designing future clinical trials.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 92%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The KHENERGY Study: Safety and Efficacy of KH176 in Mitochondrial m.3243A>G Spectrum Disorders

Janssen

Koene

Laat

et al. 2018

Clin Pharma and Therapeutics

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Moving towards clinical trials for mitochondrial diseases

Pitceathly

Keshavan

Rahman³

et al. 2020

J of Inher Metab Disea

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Primary mitochondrial diseases represent some of the most common and severe inherited metabolic disorders, affecting ~1 in 4,300 live births. The clinical and molecular diversity typified by mitochondrial diseases has contributed to the lack of licensed disease‐modifying therapies available. Management for the majority of patients is primarily supportive. The failure of clinical trials in mitochondrial diseases partly relates to the inefficacy of the compounds studied. However, it is also likely to be a consequence of the significant challenges faced by clinicians and researchers when designing trials for these disorders, which have historically been hampered by a lack of natural history data, biomarkers and outcome measures to detect a treatment effect. Encouragingly, over the past decade there have been significant advances in therapy development for mitochondrial diseases, with many small molecules now transitioning from preclinical to early phase human interventional studies. In this review, we present the treatments and management strategies currently available to people with mitochondrial disease. We evaluate the challenges and potential solutions to trial design and highlight the emerging pharmacological and genetic strategies that are moving from the laboratory to clinical trials for this group of disorders.

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The Redox Modulating Sonlicromanol Active Metabolite KH176m and the Antioxidant MPG Protect Against Short-Duration Cardiac Ischemia-Reperfusion Injury

Xiao

Yim

Zhang

et al. 2021

Cardiovasc Drugs Ther

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Purpose Sonlicromanol is a phase IIB clinical stage compound developed for treatment of mitochondrial diseases. Its active component, KH176m, functions as an antioxidant, directly scavenging reactive oxygen species (ROS), and redox activator, boosting the peroxiredoxin-thioredoxin system. Here, we examined KH176m’s potential to protect against acute cardiac ischemia-reperfusion injury (IRI), compare it with the classic antioxidant N-(2-mercaptopropionyl)-glycine (MPG), and determine whether protection depends on duration (severity) of ischemia. Methods Isolated C56Bl/6N mouse hearts were Langendorff-perfused and subjected to short (20 min) or long (30 min) ischemia, followed by reperfusion. During perfusion, hearts were treated with saline, 10 μM KH176m, or 1 mM MPG. Cardiac function, cell death (necrosis), and mitochondrial damage (cytochrome c (CytC) release) were evaluated. In additional series, the effect of KH176m treatment on the irreversible oxidative stress marker 4-hydroxy-2-nonenal (4-HNE), formed during ischemia only, was determined at 30-min reperfusion. Results During baseline conditions, both drugs reduced cardiac performance, with opposing effects on vascular resistance (increased with KH176m, decreased with MPG). For short ischemia, KH176m robustly reduced all cell death parameters: LDH release (0.2 ± 0.2 vs 0.8 ± 0.5 U/min/GWW), infarct size (15 ± 8 vs 31 ± 20%), and CytC release (168.0 ± 151.9 vs 790.8 ± 453.6 ng/min/GWW). Protection by KH176m was associated with decreased cardiac 4-HNE. MPG only reduced CytC release. Following long ischemia, IRI was doubled, and KH176m and MPG now only reduced LDH release. The reduced protection against long ischemia was associated with the inability to reduce cardiac 4-HNE. Conclusion Protection against cardiac IRI by the antioxidant KH176m is critically dependent on duration of ischemia. The data suggest that with longer ischemia, the capacity of KH176m to reduce cardiac oxidative stress is rate-limiting, irreversible ischemic oxidative damage maximally accumulates, and antioxidant protection is strongly diminished.

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

Cited by 36 publications

References 70 publications

The KHENERGY Study: Safety and Efficacy of KH176 in Mitochondrial m.3243A>G Spectrum Disorders

The KHENERGY Study: Safety and Efficacy of KH176 in Mitochondrial m.3243A>G Spectrum Disorders

Moving towards clinical trials for mitochondrial diseases

The Redox Modulating Sonlicromanol Active Metabolite KH176m and the Antioxidant MPG Protect Against Short-Duration Cardiac Ischemia-Reperfusion Injury

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