The <scp>KHENERGY</scp> Study: Safety and Efficacy of <scp>KH</scp>176 in Mitochondrial m.3243A&gt;G Spectrum Disorders

Janssen, Mirian C. H.; Koene, Saskia; Laat, Paul de; Hemelaar, Pleun; Pickkers, Peter; Spaans, Edwin; Beukema, Rypko; Groothuis, Jan T.; Verhaak, Chris M.; Smeitink, Jan A.M.

doi:10.1002/cpt.1197

Cited by 44 publications

(43 citation statements)

References 30 publications

(66 reference statements)

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“…www.nature.com/scientificreports/ Redox modulating compounds KH176 and KH176m partially reverses neuronal deficits in PRKN mutant DA neurons. In order to evaluate if the driving mechanism in PRKN mutant DA neurons is the loss of energy production by the mitochondria or the dramatically increased mitochondrial ROS production, we treated the end stage day 27 neurons with the known potent intracellular redox-modulating agents KH176 and KH176m 35 currently in clinical trials in mitochondrial patients with m.3243A>G spectrum disorders 36 . KH176 and its quinone metabolite KH176m were identified from a screen in fibroblasts from patients with primary mitochondrial diseases.…”

Section: Resultsmentioning

confidence: 99%

Oxidative switch drives mitophagy defects in dopaminergic parkin mutant patient neurons

Schwartzentruber

Boschian

Lopes

et al. 2020

Sci Rep

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Mutations in PRKN are the most common cause of early onset Parkinson’s disease. Parkin is an E3 ubiquitin ligase, functioning in mitophagy. Mitochondrial abnormalities are present in PRKN mutant models. Patient derived neurons are a promising model in which to study pathogenic mechanisms and therapeutic targets. Here we generate induced neuronal progenitor cells from PRKN mutant patient fibroblasts with a high dopaminergic neuron yield. We reveal changing mitochondrial phenotypes as neurons undergo a metabolic switch during differentiation. Fibroblasts from 4 controls and 4 PRKN mutant patients were transformed into induced neuronal progenitor cells and subsequently differentiated into dopaminergic neurons. Mitochondrial morphology, function and mitophagy were evaluated using live cell fluorescent imaging, cellular ATP and reactive oxygen species production quantification. Direct conversion of control and PRKN mutant patient fibroblasts results in induced neuronal progenitor and their differentiation yields high percentage of dopaminergic neurons. We were able to observe changing mitochondrial phenotypes as neurons undergo a metabolic switch during differentiation. Our results show that when pre-neurons are glycolytic early in differentiation mitophagy is unimpaired by PRKN deficiency. However as neurons become oxidative phosphorylation dependent, mitophagy is severely impaired in the PRKN mutant patient neurons. These changes correlate with changes in mitochondrial function and morphology; resulting in lower neuron yield and altered neuronal morphology. Induced neuronal progenitor cell conversion can produce a high yield of dopaminergic neurons. The mitochondrial phenotype, including mitophagy status, is highly dependent on the metabolic status of the cell. Only when neurons are oxidative phosphorylation reliant the extent of mitochondrial abnormalities are identified. These data provide insight into cell specific effects of PRKN mutations, in particular in relation to mitophagy dependent disease phenotypes and provide avenues for alternative therapeutic approaches.

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Section: Resultsmentioning

confidence: 99%

Oxidative switch drives mitophagy defects in dopaminergic parkin mutant patient neurons

Schwartzentruber

Boschian

Lopes

et al. 2020

Sci Rep

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“…Sonlicromanol (KH176; IUPAC chemical name (S)-6-hydroxy-2,5,7,8-tetramethyl-N-((R)-piperidin-3yl)chroman-2-carboxamide hydrochloride) is a clinical trial stage drug compound (phase 1 completed, phase 2a completed, phase 2b ongoing) (Koene et al, 2017;Beyrath et al, 2018;Janssen et al, 2019) with a triple mode of action (radical trapping, ferroptosis inhibition by inhibiting lipid peroxidation, anti-inflammatory inhibiting mPGES-1). Important in this context is that both the parent compound (sonlicromanol) and its metabolite (KH176m) are both active and, in humans, ~50% of the parent compound is converted to the active metabolite KH176m (Koene et al, 2017;Janssen et al, 2019).…”

Section: Sonlicromanol: a Clinical Trial Stage Drug Compound Selectivmentioning

confidence: 99%

Hypothesis: mPGES-1-Derived Prostaglandin E2, a So Far Missing Link in COVID-19 Pathophysiology?

Smeitink¹,

Jiang²,

Pecheritsyna³

et al. 2020

Preprint

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With frequencies varying up to 20%, treatment resistant pulmonary failure is a major life-threatening complication in COVID-19 (SARS-CoV-2, HCoV19) disease pathology. Both acute respiratory distress syndrome (ARDS), proposed to be caused by an over-reacting immune system which floods the lung with edema, a liquid consisting of inflammatory cells, and diminished lung perfusion, have been postulated to cause this treatment resistant lung failure. Aging, co-morbidities, male gender and obesity are pre-existing factors associated with the more severe outcome. Thrombosis is more frequently observed than usually seen during ICU admission. Different hypotheses explaining the pathophysiological cascade leading to fast progressing severe COVID-19 disease and how to counteract it have been proposed. A variety of intervention studies to control severity are ongoing or planned. Not suggested so far, we here hypothesize that the inflammatory lipid modulator prostaglandin E2 (PGE2) executes a prominent role in COVID-19 pathophysiology. Based on this we suggest measuring PGE2 in patients and evaluating selective inhibition of the human microsomal prostaglandin E synthase-1 (mPGES-1) as a potential innovative therapeutic approach in this devastating condition for which sonlicromanol, a drug currently in phase 2b studies for mitochondrial disease, is a candidate.

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“…We report that sonlicromanol, a compound targeting mitochondrial function, can improve both neuronal network function as well as changes in gene expression, representing mitochondrial respiration and synaptic function. Sonlicromanol has not yet been tested in a large-scale clinical trial, but the phase II clinical trial has already shown improvements in mood and alertness, often found in patients suffering from m.3243A>G related-and other mitochondrial diseases (Janssen et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Sonlicromanol improves neuronal network dysfunction and transcriptome changes linked to m.3243A>G heteroplasmy in iPSC-derived neurons

Gunnewiek

Verboven

Hogeweg

et al. 2020

Preprint

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Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is often caused by an adenine to guanine mutation at m.3243 (m.3243A>G) of the MT-TL1 gene (tRNAleu(UUR)). To understand how this mutation affects the nervous system, we differentiated human induced-pluripotent stem cells (iPSCs) into excitatory neurons with normal (low heteroplasmy) and impaired (high heteroplasmy) mitochondrial function from MELAS patients with the m.3243A>G mutation. We combined micro-electrode array (MEA) measurements with RNA sequencing (MEA-seq) and found that the m.3243A>G mutation affects expression of genes involved in mitochondrial respiration- and presynaptic function, as well as non-cell autonomous processes in co-cultured astrocytes. Finally, we show that the clinical II stage drug sonlicromanol (KH176) improved neuronal network activity in a patient-specific manner when treatment is initiated early in development. This was intricately linked with changes in the neural transcriptome. Overall, MEA-seq is a powerful approach to identify mechanisms underlying the m.3243A>G mutation and to study the effect of pharmacological interventions in iPSC-derived neurons.

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

Cited by 44 publications

References 30 publications

Oxidative switch drives mitophagy defects in dopaminergic parkin mutant patient neurons

Oxidative switch drives mitophagy defects in dopaminergic parkin mutant patient neurons

Hypothesis: mPGES-1-Derived Prostaglandin E2, a So Far Missing Link in COVID-19 Pathophysiology?

Sonlicromanol improves neuronal network dysfunction and transcriptome changes linked to m.3243A>G heteroplasmy in iPSC-derived neurons

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