Results from collaborative preclinical research effort investigating Leigh disease patient cells published in Cell Death and Disease

NIJMEGEN, the Netherlands – November 2018: Khondrion, the clinical-stage pharmaceutical company discovering and developing therapies targeting mitochondrial disease, today announces the publication of a scientific article reporting on the underlying patho-mechanism of Leigh disease and new potential therapeutic avenues in Cell Death and Disease.

The work was carried out by Khondrion’s R&D team in collaboration with the Department of Biochemistry at the Radboud University Medical Center. The study reports on the development of a cell-based strategy for intervention testing and analysis of the pathophysiological consequences and adaptive responses in cells from patients with mitochondrial complex I deficiency.

In vitro cell models of mitochondrial complex I deficiencies often display activation of glycolysis to compensate for the loss in mitochondrial ATP production, which can mask other relevant disease-induced pathological consequences. In this work, the team optimised a cell culture protocol in which the glycolysis adaptation was turned down. In the newly developed conditions, cells from Leigh disease patients died after several days of culturing, whereas cells from healthy donors did not.

Several metabolic and cellular dysfunctions were highlighted before cell death occurred, providing further understanding of the disease, to support future drug development. Of note, the results showed that Leigh disease cells could be rescued by supplementation of the culture medium with specific metabolites such as pyruvate and nicotinamide adenine dinucleotide. These two metabolites were also shown to rescue cells via different modes of action, targeting either oxidative or reductive stress, respectively.

Commenting on the study results, Dr. Julien Beyrath, Chief Operating Officer of Khondrion, said: “We are very pleased with this work, leading to the establishment of a robust in vitro assay mimicking the severity of mitochondrial disease. Such models are crucial to study and unravel the cellular consequences of mutations causing mitochondrial disease, but also to predict the potential of new therapeutics. This study provides us with newly identified pathological mechanisms and new therapeutic avenues to be further developed. Interestingly, the study points at the potential of combination therapies targeting multiple cellular consequences of mitochondrial complex I deficiency.”

Mitochondrial disease occurs when mitochondria, found within all cells of the human body and responsible for producing the energy necessary for life, are defective. This can result in a wide range of serious and debilitating illnesses, signs and symptoms of which can include: cognitive problems, learning disabilities, blindness, deafness, heart failure, diabetes, fatigue, intolerance to exercise, muscle weakness and gait problems, and stunted growth. Orphan diseases of the oxidative phosphorylation system like Leigh disease, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) spectrum disorders, MIDD (maternally inherited diabetes and deafness), LHON (Leber’s hereditary optic neuropathy) and other respiratory chain/ oxidative phosphorylation disorders, are all examples of mitochondrial disease.

Cellular consequences like abnormal mitochondrial architecture, reactive oxygen species production and alterations in the cellular redox-state are common findings in mitochondrial diseases. Khondrion’s drug development strategy is based on counteracting these cellular consequences to stop disease progression and to restore normal cellular function.

About Khondrion

Khondrion is a clinical-stage pharmaceutical company discovering and developing therapies targeting mitochondrial disease. Founded by Prof. Jan Smeitink, a world-leader in mitochondrial medicine, the company is advancing its proprietary science through a wholly-owned clinical and preclinical small molecule pipeline of potential medicines.

Khondrion’s lead asset, KH176, is a potential first-in-class oral small molecule in phase IIb clinical development to treat a range of mitochondrial diseases including MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) spectrum disorders. It has been granted Orphan Drug Designation for MELAS spectrum disorders and Leigh disease in Europe and for all inherited mitochondrial respiratory chain disorders in the USA.

The company’s in-house discovery engine is using unique live-cell imaging technologies, patient-derived cell lines and predictive cell-based disease models to build a portfolio of promising compounds. Active discovery programmes are underway developing new therapies, biomarkers and new read-out technologies in the field of mitochondrial diseases.

To accelerate the discovery and development of its potential medicines for mitochondrial diseases, Khondrion collaborates with a global clinical and academic network and patient organisations internationally. Khondrion is headquartered in Nijmegen, The Netherlands. For more information visit

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Khondrion BV

Prof. dr. Jan Smeitink, CEO


Tel: +31-24-3617505