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Developmental Biology - Precision Medicine

Therapy For Mitochondrial Disease?

An existing drug may have therapeutic potential in mitochondrial disease...

New preclinical findings from extensive cell and animal studies suggest that a drug already used for a rare kidney disease could benefit patients with some mitochondrial disorders--complex conditions with severe energy deficiency for which no proven effective treatments exist. Future clinical research is needed to explore whether the drug, cysteamine bitartrate, will meaningfully benefit patients.
"We found therapeutic potential in mitochondrial disease, based on evidence for neuroprotection in two different animal models. However, we also showed that this drug has a narrow therapeutic window - even small increases in dosage were toxic in diverse laboratory animals and human cells. This implies that dosages would need to be very carefully controlled if cysteamine bitartrate eventually were to become a precision medicine treatment option for mitochondrial disease..."

Marni J Falk MD, Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

The study team published its findings Jan. 22, 2019 in Human Molecular Genetics.

Mitochondria are tiny structures in human and animal cells that produce energy through an integrated series of chemical reactions known as the respiratory chain (RC). Mitochondria contain their own DNA, distinct from the more familiar DNA inside a cell nucleus. Because pathogenic variants in over 350 different genes across both nuclear and mitochondrial DNA genomes are now recognized to cause mitochondrial diseases, these disorders are highly complex, typically causing 16 or more symptoms per patient, and affecting multiple organs and systems.

Much of the damage in mitochondrial diseases stems from oxidative stress, in which reactive molecules disrupt energy-producing components inside the mitochondrial RC. Antioxidant compounds, by acting to defend against these free radicals, may offer some protection from mitochondrial dysfunctions.
Falk and colleagues have been systematically evaluating a variety of drug candidates in search of possible treatments for mitochondrial RC disease.

They recently found that an antioxidant called NAC (N-acetylcysteine) showed encouraging preclinical results in animal studies. Because cysteamine bitartrate, currently FDA approved to treat a rare kidney disorder nephropathic cystinosis, is thought to act on biological pathways similar to NAC, Falk's team performed their current preclinical research.
"We tested the hypothesis that cysteamine bitartrate would increase synthesis of glutathione, a potent antioxidant enzyme that humans and animals naturally produce to scavenge free radicals. Surprisingly, we learned that cysteamine bitartrate did not, in fact, increase total glutathione levels in our experiments. However, we found it had beneficial health effects that appear to result from different mechanisms than we had anticipated."

Marni J Falk MD

The researchers found an intriguing set of different benefits in three models of mitochondrial disease: human patient cells (fibroblasts), microscopic worms (C. elegans) and microscopic fish (zebrafish). Cysteamine bitartrate modestly improved mitochondrial metabolism and reproductive capacity in the worms, with reduction in oxidative stress. In the zebrafish, the drug had more dramatic benefits, preventing brain death and neuromuscular defects caused by mitochondrial RC dysfunction.

In the human fibroblast cells, from mitochondrial disease patients, the drug increased the cells' resiliency and ability to survive when subjected to chemical stressors. "Overall, treatment effects we observed in both cell and animal models of mitochondrial RC disease suggest that cysteamine bitartrate might have the potential to improve overall health and stress resiliency in human patients," said Falk. "Identifying the right kinds of antioxidant treatments at the proper dosage may be neuroprotective, potentially preventing metabolic strokes that often occur when mitochondrial disease patients are stressed by an infection or other risk factors."
Falk cautioned patients and families not to self-prescribe antioxidants for mitochondrial disease, as safe and effective dosages and appropriate usages specific to different mitochondrial disease patient outcomes are yet to be determined. In this current study, all potential benefits observed in cells and animals occurred at low concentrations, with clear toxicity at higher doses.

"Now that preclinical evidence is increasing to support the potential of antioxidant therapies to objectively benefit overall health in the setting of RC disease, better clinical tests are needed to evaluate oxidant levels and antioxidant enzyme activities, as well as mitochondrial function and clinical outcomes, in patients who receive antioxidant therapy," says Falk.

She adds that several such new clinical diagnostic tests and outcome measure assessments to facilitate this process are under development in the CHOP Mitochondrial Medicine Frontier Program. Ultimately, she concludes: "better understanding of each mitochondrial disease patient's oxidative stress and defense levels — together with carefully designed clinical trials to determine the health benefits or risks of candidate therapies — will enable a precision mitochondrial medicine approach to select optimal antioxidants and doses to improve health resiliency and outcomes for each patient."

Most studies of proteolysis by the ubiquitin-proteasome pathway have focused on the regulation by ubiquitination. However, we showed that pharmacological agents that raise cAMP and activate protein kinase A by phosphorylating a proteasome subunit enhance proteasome activity and the cell’s capacity to selectively degrade misfolded and regulatory proteins. We investigated whether similar adaptations occur in physiological conditions where cAMP rises. Proteasome activity increases by this mechanism in human muscles following intense exercise, in mouse muscles and liver after a brief fast, in hepatocytes after epinephrine or glucagon, and renal collecting duct cells within 5 minutes of antidiuretic hormone. Thus, hormones and conditions that raise cAMP rapidly enhance proteasome activity and the cells’ capacity to eliminate damaged and preexistent regulatory proteins.

Cysteamine bitartrate is a US Food and Drug Administration-approved therapy for nephropathic cystinosis also postulated to enhance glutathione biosynthesis. We hypothesized this antioxidant effect may reduce oxidative stress in primary mitochondrial respiratory chain (RC) disease, improving cellular viability and organismal health. Here, we systematically evaluated the therapeutic potential of cysteamine bitartrate in RC disease models spanning three evolutionarily distinct species. These pre-clinical studies demonstrated the narrow therapeutic window of cysteamine bitartrate, with toxicity at millimolar levels directly correlating with marked induction of hydrogen peroxide production. Micromolar range cysteamine bitartrate treatment in Caenorhabditis elegans gas-1(fc21) RC complex I (NDUFS2-/-) disease invertebrate worms significantly improved mitochondrial membrane potential and oxidative stress, with corresponding modest improvement in fecundity but not lifespan. At 10 to 100 ?M concentrations, cysteamine bitartrate improved multiple RC complex disease FBXL4 human fibroblast survival, and protected both complex I (rotenone) and complex IV (azide) Danio rerio vertebrate zebrafish disease models from brain death. Mechanistic profiling of cysteamine bitartrate effects showed it increases aspartate levels and flux, without increasing total glutathione levels. Transcriptional normalization of broadly dysregulated intermediary metabolic, glutathione, cell defense, DNA, and immune pathways was greater in RC disease human cells than in C. elegans, with similar rescue in both models of downregulated ribosomal and proteasomal pathway expression. Overall, these data suggest cysteamine bitartrate may hold therapeutic potential in RC disease, although not through obvious modulation of total glutathione levels. Careful consideration is required to determine safe and effective cysteamine bitartrate concentrations to further evaluate in clinical trials of human subjects with primary mitochondrial RC disease.

Sujay Guha Chigoziri Konkwo Manuela Lavorato Neal D Mathew Min Peng Julian Ostrovsky Young-Joon Kwon Erzsebet Polyak Richard Lightfoot Christoph Seiler Rui Xiao Michael Bennett Zhe Zhang Eiko Nakamaru-Ogiso and Marni J Falk.

Funding support for this study came from the National Institutes of Health (HD065858, GM120762, and NS007413), Raptor Pharmaceuticals, the Juliet's Cure Mitochondrial Disease Research Fund and the Will Woleben Research Fund.

Children's Hospital of Philadelphia: Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 564-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu

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Feb 27 2019   Fetal Timeline   Maternal Timeline   News  

A systematic study of seven antioxidants commonly taken by or suggested to benefit children and adults affected with mitochondrial disease give intriguing clues that at least two compounds should be further evaluated in clinical trials. Despite their growing recognition, these complex genetic disorders currently have no proven effective treatments. Credit: Children's Hospital of Philadelphia

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