Scientists from Mass General Brigham and the Broad Institute have been studying more effective ways of treating people living with Friedreich’s ataxia (FA). People with this rare and progressive neuromuscular disorder are often diagnosed between the ages of five and 15 and live into their 30s or 40s. A key challenge is that there are no widely approved treatments for the disease, and existing therapies may not be effective in all cases. But that could change thanks to a new study that sheds light on a genetic modifier of the disease, which may open a door to new treatments.
Details of the work are available in a new Nature paper titled “Mutations in mitochondrial ferredoxin FDX2 suppress frataxin deficiency.” It describes the investigators’ efforts to use Caenorhabditis elegans (C. elegans) to understand and potentially treat FA. The disease is due to the loss of a mitochondrial protein called frataxin, part of the protein machinery used to make essential co-factors called iron sulfur clusters. These are essential co-factors needed for mediating electron transfer within the mitochondrial respiratory chain among other biological processes.
The current findings build on previous work from the laboratory of Vamsi Mootha, MD, an institute member at the Broad Institute and a professor in the departments of systems biology at Harvard Medical School and medicine at Massachusetts General Hospital (MGH). That earlier study showed that hypoxic conditions can partially rescue frataxin loss in human cells, worms, and mice.
“In this paper, instead of trying to pursue hypoxia to slow or postpone the disease as a therapy, we simply used it as a trick. We used it as a laboratory tool with which to discover genetic suppressors,” said Joshua Meisel, PhD, lead and co-corresponding author on the current Nature study. Meisel is a former postdoctoral fellow at MGH and a founding member of the Mass General Brigham healthcare system. He is now an assistant professor at Brandeis University. “The reason this is exciting is because the suppressor that we’ve identified, FDX2, is now a protein that can be targeted using more conventional medicines.”
To get to that insight, Meisel, Mootha, and their collaborators created worms that completely lacked frataxin and grew them in low-oxygen conditions, which allowed these otherwise non-viable roundworms to survive. They then introduced random genetic changes into the worms and looked for individuals that grew successfully even when oxygen levels were higher—a situation that should have been fatal to frataxin-deficient worms.
Next, they sequenced the genomes of the survivors. This allowed them to identify specific mutations in two other mitochondrial genes, FDX2 and NFS1 that allowed the survivors to bypass the need for frataxin and still produce essential iron-sulfur clusters. As part of the study, the scientists confirmed the effects of the mutations using biochemical tests and experiments in both human cells and mice.
Furthermore, their analysis showed that too much FDX2 can block iron-sulfur cluster synthesis. Conversely, reducing FDX2, either by introducing a new genetic mutation or removing a copy of the gene, restores production. “The balance between frataxin and FDX2 is key,” Mootha said. “When you are born with too little frataxin, bringing down FDX2 a bit helps. So, it’s a delicate balancing act to ensure proper biochemical homeostasis.”
To see if their findings could translate to an effective treatment strategy, the scientists tested the effects of lowering FDX2 levels in a mouse model of FA. They report that indeed the approach improved neurological symptoms in the mouse.
It is preliminary evidence but promising. The researchers note that the precise balance of frataxin and FDX2 needed for healthy cells may vary depending on the situation, and more work is needed to understand how this balance is regulated in people. Future studies will need to test whether adjusting FDX2 levels is safe and effective as an FA therapy in additional pre-clinical models before human trials are a possibility.
