Preclinical Study Shows Combination of Vitamins, Supplements May Benefit Mitochondrial Disease

Marni Falk and her team found a combination of vitamins and supplements may be an effective treatment for mitochondrial disease.

shafere1 [at] chop.edu (By Emily Shafer)

A lack of approved therapies for mitochondrial disease leads many patients to seek therapy with vitamins and supplements; however, these treatments have not been evaluated in clinical trials. Researchers from Children's Hospital of Philadelphia are working to change that, and they recently identified a trio of drugs that together may be a potential effective treatment.

In a preclinical study, they found that a combination of glucose, nicotinic acid, and N-acetylcysteine — all vitamins or supplements that are available over the counter — appears to be beneficial for patients with mitochondrial respiratory chain disorders. The study team reported their findings in Human Molecular Genetics.

Mitochondrial disease comprises a group of energy deficiency disorders that impair mitochondrial respiratory chain function, which is necessary to make energy to power cells in the body. Physicians often recommend vitamins to patients, but there is no definitive knowledge about how much to take, or what formulation to take, or if there is any value to combining several types of vitamins or supplements.

"We've gotten a lot smarter about the genetics of mitochondrial disease, and the biochemical processes that are disrupted by mitochondrial energy failure," said Marni J. Falk, MD, executive director of the Mitochondrial Medicine Frontier Program at CHOP, and senior author of the study. "We know that vitamins and supplements change many processes in cell physiology, In the setting of mitochondrial disease, where there occurs major deficiencies and disruptions of several of these same physiologic processes, there may be actual therapeutic value of these compounds when used as drugs. But they also have the potential for having toxic effects in mitochondrial disease patients, where dose and combinations used can really matter".

In previous research, Dr. Falk, who is also professor of Pediatrics at Perelman School of Medicine at the University of Pennsylvania, and her research team identified three different classes of therapies that appear to have benefits in mitochondrial disease: antioxidants, metabolic modifiers, and signaling modifiers. Antioxidants work to scavenge free radicals, which are often excessively generated in mitochondrial disease. Metabolic modifiers work by changing a specific metabolic pathway, such as cellular fat metabolism, sugar metabolism, and/or amino acid metabolism. Signaling modifiers work by targeting cellular signaling pathways that are disrupted in response to a disease process.

"Our preclinical study demonstrates that identifying the right combination of therapies that is rationally-designed based on addressing the unique cellular deficiencies of major mitochondrial disease classes can provide clear, measurable survival benefits over individual therapies that each address only part of the cellular problem," Dr. Falk said.

First author Sujay Guha, PhD

Dr. Falk and her study team, including first authors Sujay Guha, PhD, and Neal D. Mathew, PhD, evaluated 11 random combinations of drugs selected from each of the three drug classes. They studied the combinations in two translational models of mitochondrial respiratory chain complex I disease.

Working with an invertebrate microscopic worm model, they found that only the combination of glucose, nicotinic acid, and N-acetylcysteine resulted in synergistic rescue of the complex I disease animals' short lifespan. This particular therapy combination also improved mitochondrial membrane potential, a quantitative measurement of how well mitochondria make energy, without exacerbating their oxidative or mitochondrial stress.

The researchers then performed validation studies in a vertebrate zebrafish model of complex I disease. In this model, the combination therapy prevented stress-induced brain death, suggesting that the therapy may potentially prevent metabolic strokes that occur with stress in some mitochondrial disease syndromes. The combination therapy also rescued the larval zebrafish animals' swimming capacity, as well as their tissue levels of cellular energy in the form of ATP and their major antioxidant defense system, glutathione.

"It is important to translate these research insights into future clinical studies that test whether this optimized combinational therapy regimen improves health and provides resiliency to prevent clinical disease progression in mitochondrial disease patients," Dr. Falk said.