Findings point to path forward for treatment of rare genetic disease

Friedreich’s ataxia (FA) is a rare but devastating genetic disorder. Those with the condition are often diagnosed between 5 and 15 years of age and live only into their 30s or 40s. There is no widely approved treatment that modifies the disease, and existing therapies may not be effective for all patients. Researchers from Mass General Brigham and the Broad Institute, who are seeking better drug therapies to improve outcomes, describe a genetic modifier of the disease — a key insight that points to a path for new treatment. Their findings are published in Nature.

The investigators, who are using some of the most humble but important model organisms to understand and treat FA, have had their results confirmed by a biochemical analysis published by an independent research group in the same issue of Nature.

FA occurs due to the loss of a key mitochondrial protein called frataxin, which is a part of the protein machinery that makes essential co-factors called iron sulfur clusters. In previous work, the Mootha lab showed that breathing low oxygen (hypoxia) 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 lead and co-corresponding author Joshua Meisel, a former postdoctoral fellow at Massachusetts General Hospital (MGH), a founding member of the Mass General Brigham healthcare system. Meisel 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 understand how cells might overcome the loss of frataxin, the researchers, including Nobel laureate Gary Ruvkun, PhD, used a tiny roundworm called C. elegans as a model. They created worms that completely lacked frataxin and grew them in low-oxygen conditions, which allowed these otherwise non-viable roundworms to survive. The team then randomly introduced genetic changes and looked for rare worms that could grow even when oxygen levels were higher (a normally lethal situation for frataxin-deficient worms).

By sequencing the genomes of these survivors, the scientists identified specific mutations in two other mitochondrial genes, FDX2 and NFS1. They confirmed the effects of these mutations using advanced genetic engineering, biochemical tests in the lab, and experiments in both human cells and mice, to see if similar strategies could help in more complex organisms.

The study found that certain mutations in FDX2 and NFS1 can “bypass” the need for frataxin, allowing cells to better produce essential iron-sulfur clusters even when frataxin is missing. These clusters are vital for energy production and other cell functions. The researchers showed that too much FDX2 can block this process, but reducing FDX2 — either by genetic mutation or by removing one copy of the gene — restores iron sulfur cluster synthesis and cell health.

“The balance between frataxin and FDX2 is key,” said senior and co-corresponding author Vamsi Mootha, MD, of the Department of Molecular Biology and Center for Genome Medicine at MGH. Mootha is also an institute member and co-director of the Metabolism Program at Broad, and leader of the Friedreich's Ataxia Accelerator at the Broad. “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.”

Importantly, lowering FDX2 levels in a mouse model of FA improved neurological symptoms, suggesting a new potential treatment strategy. Overall, the work reveals that carefully adjusting the levels of proteins that genetically interact with frataxin could help counteract the effects of its loss in disease.

While these findings are 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. Importantly, future studies will be needed to test whether adjusting FDX2 levels is safe and effective as a therapy for FA in more pre-clinical models before contemplating human trials.

In addition to Meisel, Mootha, and Ruvkun, authors include Pallavi R. Joshi, Amy N. Spelbring, Hong Wang, Sandra M. Wellner, Presli P. Wiesenthal, Maria Miranda, Jason G. McCoy, and David P. Barondeau.

Adapted from a Mass General Brigham press release.