FA treatment shows potential to protect nerve cells
Leriglitazone extends neuron survival, boosts mitochondrial function
Leriglitazone, an oral therapy being investigated as a Friedreich’s ataxia (FA) treatment, extends nerve cell survival, improves mitochondrial function, helps balance iron levels, and prevents ferroptosis (a type of iron-dependent cell death), a cell-based study showed.
Data also showed that combining leriglitazone with lower doses of the approved FA therapy Skyclarys (omaveloxolone) may help reduce side effects while maintaining efficacy.
“The results strongly suggest that leriglitazone should be considered a potential candidate to treat FA, either alone or in combination with [Skyclarys],” the researchers wrote in the study, “Leriglitazone improves iron homeostasis and ferroptotic markers in frataxin-deficient dorsal root ganglia neurons,” published in Biomedicine & Pharmacotherapy.
FA patients are deficient in a protein called frataxin. This protein supports the functioning of mitochondria (the cell’s main energy source) and regulates iron balance. It’s thought that a lack of frataxin leads to iron overload in mitochondria, leaving cells susceptible to a type of iron-dependent cell death known as ferroptosis.
Changes in frataxin levels primarily affect cells in the heart, the cerebellum, the brain region that coordinates voluntary muscle movement, and the dorsal root ganglia (DRG), an area of the spinal cord that relays sensory information from the body to the brain. FA symptoms include ataxia (lack of muscle control and coordination), muscle wasting, and cardiomyopathy (a disease of the heart muscle).
Diving into treatment’s mechanism
Leriglitazone (MIN-102), developed by Minoryx Therapeutics, is an activator of the PPAR-gamma pathway. This pathway plays an essential role in regulating mitochondrial function and is impaired in FA.
In preclinical studies, leriglitazone boosted frataxin levels and reduced neuronal degeneration in FA cell and animal models.
Top-line data from a proof-of-concept Phase 2 study called FRAMES (NCT03917225) suggested that leriglitazone prevented ataxia progression, reduced brain iron accumulation, and improved a series of metabolic biomarkers. However, its effects on disease progression in the spinal cord, the study’s main goal, were inconclusive.
Researchers in Spain, collaborating with scientists at Minoryx, further investigated leriglitazone’s mechanism of action using lab-grown frataxin-deficient neurons (nerve cells) from rat DRG.
The scientists found leriglitazone prevented the reduction in frataxin levels in frataxin-deficient DRG neurons and significantly extended their survival. It also corrected mitochondrial functional defects in both rat DRG neurons and FA patient fibroblasts, a connective tissue cell.
The mitochondria in frataxin-deficient DRG neurons had more than twice the iron as their normal counterparts and showed signs of oxidative stress, which occurs when toxic reactive oxygen species outnumber the antioxidants that neutralize them. Leriglitazone fully normalized mitochondrial iron levels and prevented the buildup of reactive oxygen species.
“These results show that iron metabolism alterations in DRG neurons are pronounced and represent one of the possible factors that accounts for the vulnerability of frataxin-deficient neurons,” the team wrote. “In this context, leriglitazone is able to restore all these alterations by exerting a protective role.”
The oxidation of fat-like lipids, called lipid peroxidation, is known to drive ferroptosis, which can be triggered by iron-mediated oxidative stress and by impairment of the antioxidant system. Frataxin-deficient DRG neurons showed signs of lipid peroxidation and a marked decrease in antioxidants, while treatment with leriglitazone reduced or fully prevented both these defects.
Low frataxin levels in DRG neurons also reduced the levels of NrF2, a protein that activates genes to promote mitochondrial function and boost antioxidant responses. PPAR-gamma signaling was also impaired. Leriglitazone treatment significantly increased total NrF2 levels and prevented a decrease in a marker for PPAR-gamma signaling.
Skyclarys is an oral treatment approved to slow or prevent the progression of FA in adults and certain adolescents by boosting NrF2 activity. The scientists noted that some Skyclarys-treated patients have experienced side effects, like increases in markers for liver injury, leading to dose reductions.
They treated frataxin-deficient DRG neurons with either leriglitazone alone, Skyclarys alone, or both. Treatment alone or in combination resulted in a significant increase in cell survival.
All treatments significantly improved mitochondrial function, with the best results achieved with either leriglitazone alone or combining both therapies. At lower doses, Skyclarys alone was unable to improve mitochondrial function unless it was combined with leriglitazone.
“All these results suggest that lowering the dose of [Skyclarys] could affect its efficacy, but in combination with leriglitazone, this efficacy could be restored,” the team wrote.
The study “revealed leriglitazone’s potential role in reversing most of the effects of frataxin deficiency in DRG neurons alone,” the researchers concluded. The study also showed “its potential use in monotherapy and in combination with [Skyclarys] as a valuable addition to [Skyclarys]-based regimens for more robust and clinically meaningful treatment of FA.”
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