Study of the Week: Scientists Discover a Potential Therapy for an Aggressive Form of Mitochondrial Disease

Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.

If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.


This week’s study is…

Dichloroacetate improves mitochondrial function, physiology, and morphology in FBXL4 disease models

We previously published about this research in a story titled “Researchers Unearth Potential Therapy for FBXL4 Mitochondrial Disease” which can be found here. The study was originally published in the scientific journal JCI Insight. You can read the full text of the study here

This research team was affiliated with the Children’s Hospital of Philadelphia.

What Happened?

Mitochondrial disease encompasses a wide range of medical conditions that can cause varied symptoms and also range widely in severity. The principal connection between them is that they are caused by problems with the mitochondria, a cell organelle that plays a critical role in energy production. Primary mitochondrial diseases are the result of genetic mutations; one of the more severe forms that has been discovered is FBXL4 mitochondrial disease, which is linked to variant mutations in the FBXL4 gene. First described a decade ago, researchers have been struggling to find a potential therapy. This study represents a potential step forward.

The team tested 12 potential therapy candidates on a microscopic roundworm (C. elegans) model of the disease that they developed. From the 12 that were tested, the drug dichloroacetate (DCA) appeared to be the most promising. It was able to produce clear benefits to mitochondrial function and neuromotor activity. Further evaluations were conducted with DCA on human FBXL4 patient fibroblast cells and on a zebrafish (D. rerio) model. These tests confirmed the earlier findings, with DCA treatment preventing mitochondrial dysfunction, stressor-induced brain death, and impairments of muscle and neurological function.

These results have led the researchers to conclude that DCA could be a useful therapy for FBXL4 mitochondrial disease and should be evaluated in the clinical trial setting.

About Mitochondrial Disease

Mitochondrial disease is a group of genetic disorders that cause the mitochondria not to function properly. The mitochondria are an essential organelle that is found in most types of cells in the body, with red blood cells being the only exception. They are responsible for generating energy for the cell. Mitochondrial disease is usually caused by mutations of the mitochondrial DNA or the nuclear DNA. Symptoms tend to be the worst when the issue affects cells that use a lot of energy, such as the muscles or parts of the brain. These symptoms affect many aspects of bodily function and include poor growth, poor muscle coordination, dementia, neurological issues, muscle weakness, breathing disorders, vision problems, digestive disorders, hearing problems, disease of the kidney, liver, and heart, and learning disabilities. Treatment options are limited in number and in their effectiveness. To learn more about mitochondrial disease, click here.

Why Does it Matter?

As a whole, treatments for mitochondrial diseases are extremely limited at present. This is especially true for severe forms like FBXL4, where there is a major unmet medical need.

“These are typically very sick children. Since the gene that caused this form of mitochondrial disease was discovered by our research group a decade ago, we have been striving to find an intervention of true therapeutic value. This study is truly the culmination of translating basic research into clinically relevant findings that represents an enormous breakthrough in understanding how we might be able to improve the health of these patients, along with the breadth of cellular effects that treatment may have.” – Marni Falk, MD, Professor of Pediatrics and Executive Director of the Mitochondrial Medicine Program, Children’s Hospital of Philadelphia, Senior Study Author

There is a long way to go in the field of mitochondrial diseases, which as a whole are not particularly well understood. Discoveries like these are critical steps towards improving the lives of these rare patients, who often have no disease-altering treatment options. 

“We observed not only a reduction in tissue lactate levels but an improvement in mitochondria content when the FBXL4 disease models were treated with DCA. With no other approved options, we believe our positive findings regarding DCA for the treatment of FBXL4  should lead to its rigorous clinical study in human patients.” – Manuela Lavorato, Ph.D. research assistant professor, University of Pennsylvania School of Medicine, First Author

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