Study identifies promising therapeutic target for Friedreich’s ataxia
Targeting lipid enzymes reverses disease features in cell and mouse models
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Targeting enzymes that control how cells process fatty molecules called sphingolipids may offer a promising new treatment strategy for Friedreich’s ataxia (FA), a study in cells and mice has found.
Researchers discovered that enzymes involved in sphingolipid metabolism were disrupted in several cellular models of the disease. Targeting two of these enzymes with two experimental compounds boosted production of frataxin, the protein deficient in FA, while reversing several disease-related abnormalities in both cell and animal models.
The findings identify “sphingolipid metabolism as a promising therapeutic target for [FA],” researchers wrote, while noting that “long-term efficacy studies … are needed to fully evaluate sustained therapeutic benefits and disease modification” effects of these compounds.
The study, “Dysregulation of sphingolipid-metabolizing enzymes in Friedreich’s ataxia: In vitro and in vivo insights into therapeutic targeting,” was published in iScience.
Some sphingolipids promote cell survival; others promote cell death
FA is a genetic disease caused by mutations in the FXN gene that provides instructions for making frataxin, a protein found in mitochondria — the structures that function as cells’ powerhouses. Frataxin is essential for making iron-sulfur clusters, tiny molecular structures that many proteins need to work properly, including those involved in energy production.
As a consequence of these mutations, too little frataxin is produced, and mitochondria cannot work properly. Iron accumulates within cells, leading to oxidative stress (a type of cellular damage) and, ultimately, cell death. Nerve cells and heart muscle cells, which have especially high energy demands, are among the most affected, leading to the progressive neurological and heart problems that characterize FA.
Skyclarys (omaveloxolone), the first and only treatment specifically approved for FA, works by activating Nrf2, a protein that switches on the cell’s natural defenses against oxidative stress. While the treatment has been shown to improve neurological function, its effects on other aspects of the disease, including heart disease, remain unclear. As such, researchers continue to explore additional treatment approaches that could address the broader range of symptoms and complications associated with FA.
One pathway attracting increasing interest involves sphingolipids, a family of fatty molecules that help regulate how cells respond to stress. Some sphingolipids promote cell survival, while others promote cell damage and death; cells normally maintain a dynamic balance between these molecules.
Previous studies, however, have suggested that this balance is disrupted in FA. Given the evidence linking sphingolipid dysregulation to hallmark events of FA, such as altered iron metabolism, oxidative stress, and cell death, the researchers wondered whether the enzymes that control these molecules might also be disrupted and whether targeting them could ameliorate disease-related abnormalities.
Researchers employ multiple cell models
In this study, a team of researchers from the U.K. and Spain turned to several lab models of FA, including skin cells from people with FA grown in the lab, and sensory nerve and heart cells generated from patients’ induced pluripotent stem cells (iPSCs), which are adult cells reprogrammed into a stem cell-like state that allows them to grow into many different types of cells.
Cerebellar tissue from an FA mouse model was also analyzed. The cerebellum is a brain region that helps control balance and coordination and is affected by the disease.
Across the different lab models, the researchers found evidence that the balance between different sphingolipid-metabolizing enzymes was disrupted.
In skin cells from people with FA, they found reduced levels and activity of the sphingosine kinase (SPHK) enzymes, which help produce sphingolipids that promote cell survival, and increased levels and activity of the lipid phosphate phosphatase (LPP) enzymes, which shift the balance toward sphingolipids associated with cell stress and death.
Changes in levels of different SPHK and LPP enzymes were also observed in other lab models, although the specific changes differed between cell types.
Treating skin cells from people with FA with K6PC-5, an experimental compound that activates SPHK, or XY-14, which blocks LPP, significantly increased activity levels of the FXN gene. XY-14 also significantly increased frataxin protein levels, suggesting “that sphingolipids may modulate pathways controlling frataxin expression,” the team wrote.
Cells treated with XY-14 were better able to survive oxidative stress
Both compounds also improved several measures linked to mitochondrial function and increased levels of Nrf2. Cells treated with XY-14 were also better able to survive oxidative stress. K6PC-5 and XY-14 also lowered free iron levels inside cells, suggesting that targeting sphingolipids “could reduce oxidative stress by modulating iron levels,” the researchers wrote.
Most of the findings were also confirmed in sensory nerve cells derived from iPSCs of people with FA, suggesting the approach may benefit the cells most affected by the disease.
In a mouse model of FA, four days of treatment increased frataxin protein levels in the cerebellum, and the increase was statistically significant in mice treated with XY-14. The compounds also improved several markers of mitochondrial function.
“This study identified dysregulation of sphingolipid-metabolizing enzymes in [FA], particularly SPHK and LPP, across various models,” the researchers wrote.
While further studies are needed to assess whether the compounds can ease disease symptoms and slow disease progression, the results suggest that targeting these enzymes may represent “a promising therapeutic target for [FA],” the team concluded.
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