Researchers from the Mitochondrial Medicine Frontier Program at the Philadelphia Children’s Hospital (CHOP) have shown how a combination of therapies can be beneficial for patients with mitochondrial diseases of the respiratory chain.
This preclinical research paves the way for the development of more tailored treatment options for patients with hereditary mitochondrial diseases and acquired energy disorders. The results underscore the importance of rational therapeutic modeling to target specific cellular deficiencies and provide adequate cell nutrition as an effective means of treating mitochondrial disease.
The results were published online by the journal Human Molecular Genetics.
Mitochondrial diseases describe a collective group of energy deficiency diseases with no FDA-approved treatments or cures. It has been shown that around 350 different genetic disorders significantly impair the functioning of the mitochondrial respiratory chain, an essential process in order to generate energy for the energy supply of our cells.
The function of the respiratory chain can also be severely impaired by other genetic diseases, certain drugs or environmental influences as well as frequent metabolic disorders, strokes, heart attacks, the aging process and Alzheimer’s and Parkinson’s diseases.
In the absence of FDA-approved therapies, many affected patients seek a variety of vitamins, supplements, and enzyme cofactors or “helper molecules” that generally fall into three different treatment classes: antioxidants, metabolic modifiers, and signal modifiers.
However, rigorous clinical studies have not been conducted for these compounds to assist the medical community in understanding their comparative safety or utility in patients with mitochondrial diseases. In addition, prior to this study, it was not known whether the best options were to give certain therapies alone, or whether a combination of therapies was actually safe to administer and potentially act synergistically to provide direct health benefits to patients.
We wanted to test unique combinatorial treatment regimens in preclinical models of mitochondrial disease to see if they showed objective and measurable health benefits, and to see if some combinations are more effective than others. This modeling approach would show us where physiology is being improved the most and take the guesswork out of developing treatment options for our patients. “
Marni Falk, MD, Senior Writer and Professor, Human Genetics Division, Attending Physician, Executive Director, Borders Mitochondrial Medicine Program, Philadelphia Children’s Hospital
The study team, which included Mitochondrial Medicine team members Sujay Guha, PhD, and Neal D. Mathew, PhD, used two translational animal models of Mitochondrial Respiratory Chain Complex I Disease – the most common biochemical site for dysfunction in mitochondrial disease – to 11 random combinations to evaluate drugs selected from each of the three treatment classes.
Of these combinations, only one combination – glucose, nicotinic acid, and N-acetylcysteine - synergistically improved the first model’s lifespan beyond each component, as well as mitochondrial membrane potential, a quantitative measure of how well mitochondria are performing their essential energy-producing function.
Importantly, this combination treatment resulted in these improvements in survival and cell physiology without exacerbating negative side effects such as oxidative or mitochondrial stress.
Validation studies conducted in the second model, the zebrafish, showed that the combination therapy of glucose, nicotinic acid, and N-acetylcysteine prevented stress-induced brain death – a sign that this therapy can prevent metabolic strokes such as those found in stress in Leigh Syndrome, other mitochondrial disease syndromes occur – and rescued swimming ability of larval zebrafish, as well as their tissue levels of ATP and glutathione.
“The variable combinations of therapies for the treatment of patients with mitochondrial diseases usually include empirically sound” cocktails “made from vitamins and nutrients, the safety and effectiveness of which are difficult to evaluate and compare objectively,” said Falk.
“Our preclinical study shows that identifying the right combination of therapies, rationally engineered based on treating the unique cellular deficiencies of the major classes of mitochondrial disease, offers clear, measurable survival and health benefits over individual therapies that are only a subset of each Addressing the Cell Problem It is important to translate this research into future clinical trials to see if these optimized combinatorial therapies improve health and increase resilience to prevent the progression of clinical disease in patients with mitochondrial disease. “
Philadelphia Children’s Hospital
Guha, S. et al. (2021) The combinatorial therapy with glucose, nicotinic acid and N-acetylcysteine works synergistically in preclinical C. elegans and zebrafish models of mitochondrial complex I disease. Human genetics. doi.org/10.1093/hmg/ddab059.