Researchers have found an effective combination of treatments for managing mitochondrial disease

The study is the first to demonstrate how a single combination therapy may provide measurable benefits for patients with mitochondrial respiratory chain disorders, which currently lack FDA-approved therapies.

PHILADELPHIA, March 2, 2021 – Researchers from the Mitochondrial Medicine Frontier Program at Children’s Hospital of Philadelphia (CHOP) show how one set of treatments can be beneficial for patients with mitochondrial respiratory chain disorders. This preclinical research paves the way for the development of more customized treatment options for patients with inherited mitochondrial diseases and acquired energy disorders. The results emphasize the importance of rational therapeutic modeling for targeting specific cellular deficiencies and providing appropriate cellular nutrition as an effective method for managing mitochondrial disease.

The results have been published online by the journal Human Molecular Genetics.

Mitochondrial disease describes a collective group of energy deficiency disorders without treatments or treatments approved by the Food and Drug Administration. Approximately 350 different genetic disorders have been shown to significantly impair the function of the mitochondrial respiratory chain, a process essential for generating energy to power our cells. The function of the respiratory chain can also be severely disrupted by other genetic conditions, certain medications, or environmental exposure, as well as common metabolic disorders, strokes, heart attacks, the aging process, and Alzheimer’s and Parkinson’s disease.

In the absence of FDA-approved therapies, many affected patients seek or prescribe a variety of vitamins, supplements, and enzymatic cofactors or “helper molecules,” which generally fall into three different treatment categories: antioxidants, metabolic modifiers, and And signal rates. However, rigorous clinical trials of these compounds have not been performed to guide the medical community in understanding their relative safety or benefit in patients with mitochondria. Additionally, prior to this study, it was not known whether the best options would be to administer specific therapies on their own or whether a combination of treatments is truly safe to administer and may work synergistically to provide patients with any direct health benefit.

“We wanted to test unique combinational therapy regimens in preclinical models of mitochondrial disease to determine whether they showed any objective and measurable benefit to health, and to see whether some combinations might be more effective than others,” said lead author Marnie Falk, MD. . , Professor in the Department of Human Genetics as well as Attending Physician and Executive Director of the Frontier Mitochondrial Medicine Program (CHOP). “This modeling approach will show us where physiology is greatly improved, and it will take the guesswork out of developing treatment options for our patients.”

The study team, including members of the mitochondrial medicine team, Sujay Guha, Ph.D. and Neil D. Matthew, Ph.D., used two multiple animal models of mitochondrial respiratory chain disease 1 – the most common biochemical site for dysfunction in mitochondrial disease – to evaluate 11 combinations. A randomized selection of drugs from each of the three treatment classes. Among these groups, only one combination – glucose, nic acid, and N-acetylcysteine ​​- synergistically improved the lifespan of the first form after any single component alone, as well as mitochondrial membrane potentials, which is a quantitative measure of how well mitochondria perform the primary energy production function. Importantly, this combination therapy resulted in improvements in survival and cellular physiology without exacerbating any negative side effects, such as oxidative stress or mitochondria. Verification studies conducted in the second model, zebrafish, have shown that glucose, nic acid, and N-acetylcysteine ​​combination therapy prevent stress-induced brain death – a sign that this treatment may prevent metabolic strokes such as those that occur with stress in Leigh syndrome and other mitochondrial disease syndromes – zebrafish larvae have been rescued from swimming ability in addition to tissue levels of ATP and glutathione.

“The variable combinations of treatments used to manage patients with mitochondria tend to include trial-based” cocktails “of vitamins and nutrients whose safety and effectiveness are difficult to assess objectively, Falk said. “Our preclinical study demonstrates that identifying the right combination of rationally designed therapies based on addressing the unique cellular deficiencies of major categories of mitochondrial diseases can provide clear and measurable benefits for survival and health over individual treatments that each address only part of the cellular problem. These research insights into future clinical studies that test whether these improved harmonic therapy regimens improve health and provide flexibility to prevent clinical disease progression in patients with mitochondria.


This work was supported by National Institutes of Health granting R01-HD065858, R01-GM120762, R35-GM134863, and T32-NS007413.

Guha et al, “Synthesized glucose, nic acid, and N-acetylcysteine ​​therapy has a synergistic effect in C models. Hum Mall Genet, Online February 27, 2021. DOI: 10.1093 / hmg / ddab059.

About Children’s Hospital of Philadelphia: Children’s Hospital of Philadelphia was established in 1855 as the nation’s first children’s hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of child healthcare professionals, and pioneering major research initiatives, Children’s Hospital has strengthened many discoveries that benefit children around the world. Its Pediatric Research Program is among the largest in the country. In addition, the unique family-centered care and public services programs have brought the 595-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http: // www.Cuts.Edo.

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