CHOP Researchers Develop First Viable Preclinical Model for Rare Form of Mitochondrial Disease

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Marni Falk, MD Marni Falk, MD Researchers from the Mitochondrial Medicine program at Children’s Hospital of Philadelphia (CHOP) have established the first viable preclinical model of a rare form of mitochondrial disease, which helped identify whether commonly recommended supplements or newer drug therapies may hold true therapeutic benefit for patients with this form of the disease. The findings were recently published in the journal JCI Insight.

Mitochondrial disease describes a heterogeneous group of energy disorders. In this study, researchers focused on dihydrolipoamide dehydrogenase (DLD) deficiency, a rare autosomal recessive mitochondrial disorder that disrupts several enzyme complexes needed to break down nutrients in the cells, such as certain amino acids and glucose byproducts, leading to buildup of lactic acid in the body’s tissues. As in many mitochondrial disorders, DLD deficiency can affect multiple organs and cause a range of health symptoms including Leigh syndrome, neurodevelopmental problems, low energy, and liver disease.

To study DLD deficiency and identify potential therapeutic candidates, the researchers created a preclinical C. elegans or roundworm model to study the effects of the disease. They demonstrated that DLD deficiency significantly altered the model’s survival and health, affecting its size, length, and neuromuscular function, and also activated its mitochondrial stress response.

The researchers then tested several different supplement and drug candidates that have been suggested or used as potential treatments for patients living with DLD deficiency. Not all drug candidates tested in the study demonstrated health benefits. However, dichloroacetate and thiamine (vitamin B1) each had therapeutic benefits in the model, with greater synergistic benefit when given together, suggesting they should be studied in future clinical trials of human patients living with DLD disease.

“Most mitochondrial diseases have no approved therapeutic options, so finding ways to effectively and quickly identify precision therapies is of enormous benefit to the patient community,” said Marni Falk, MD, Professor of Pediatrics and Executive Director of the Mitochondrial Medicine Program at CHOP and senior author of the study. “This living preclinical model will allow us to objectively study the effects of potential therapies on key health outcomes such as survival, growth, and mitochondrial function.”

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