Skyclarys improves nerve cell function in new Friedreich’s ataxia lab study
Lab findings show treatment reduced oxidative stress and cell damage
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Skyclarys (omaveloxolone) improved key measures of function and cellular health in nerve cells from the dorsal root ganglia, clusters of sensory nerve cells next to the spinal cord that are affected early in Friedreich’s ataxia (FA), according to a cell-based study.
The researchers also found that combining low doses of Skyclarys with a naturally occurring molecule called honokiol improved mitochondrial function and cell survival to a similar extent as higher doses of Skyclarys alone in these lab-grown nerve cells.
“These findings demonstrate the beneficial effects of [Skyclarys] and further suggest that combination therapy with honokiol may provide an effective strategy for the treatment of FA, potentially mitigating adverse effects,” the researchers wrote.
The study, “Targeting frataxin deficiency in DRG neurons and fibroblasts: omaveloxolone restores metabolic and iron balance to reduce ferroptosis,” was published in Biomedicine & Pharmacotherapy.
Frataxin deficiency disrupts mitochondrial function in Friedreich’s ataxia
FA is caused by a deficiency in frataxin, a protein essential for proper mitochondrial function. Mitochondria are structures inside cells that generate most of the cell’s energy. Without enough frataxin, mitochondria cannot properly regulate iron, which leads to increased production of harmful molecules called reactive oxygen species.
These changes mainly affect tissues with high energy demands, including muscles, the heart, the cerebellum (a brain region involved in coordinating movement), and the dorsal root ganglia (DRG).
The DRG are clusters of sensory nerve cells located next to the spinal cord that help transmit signals from the body to the brain and spinal cord. In FA, these nerve cells are especially vulnerable to damage caused by oxidative stress, when reactive oxygen species outnumber the body’s antioxidant defenses.
Skyclarys, marketed by Biogen, is an oral therapy approved to treat FA in adults and certain adolescents. It works by activating a protein called Nrf2, which helps regulate antioxidant defenses and supports mitochondrial function.
“However, [Skyclarys’] role in DRG sensory neurons, the cells that are affected the most and the earliest, is largely unknown,” the researchers wrote.
To investigate this, researchers in Spain studied frataxin-deficient DRG neurons grown in laboratory cultures from rats.
In these lab-grown rat nerve cells, Skyclarys increased frataxin levels, improved mitochondrial function, and reduced markers of cell stress and death. The treatment also improved iron regulation and lowered oxidative stress.
Skyclarys improves mitochondrial function in nerve cell lab models
Lipid peroxidation — a key marker of ferroptosis, a form of iron-dependent cell death — was elevated in frataxin-deficient neurons but was almost completely reversed after treatment with Skyclarys. Additionally, Skyclarys increased levels of Nrf2, which were suppressed in frataxin-deficient DRG neurons, and prevented abnormal increases in TFR1, the main protein involved in iron uptake.
To confirm these findings in another cell type, the researchers treated fibroblasts (connective tissue cells) derived from people with FA and from healthy individuals with Skyclarys. Similar improvements were seen in these fibroblasts. Skyclarys improved mitochondrial function, reduced iron buildup and lipid peroxidation, restored antioxidant balance, and increased Nrf2 activity in the cell nucleus.
In previous research, the team found that a naturally occurring molecule called honokiol improved mitochondrial function and reduced reactive oxygen species levels in frataxin-deficient rat DRG neurons. In this study, they tested a combination of low doses of Skyclarys and honokiol in these cells, an approach that may help reduce Skyclarys-related side effects by allowing lower doses.
In frataxin-deficient neurons, both compounds — alone or in combination — led to a significant increase in the number of surviving cells compared with untreated neurons. The combination also had a synergistic effect, meaning the two compounds worked together to improve mitochondrial function more effectively than either alone.
“The present study demonstrated, for the first time, that [Skyclarys] counteracts the majority of frataxin-deficiency-induced effects in DRG neurons,” the researchers concluded. “Most of these findings were also observed in fibroblasts from FA patients.”
