Interferon gamma helps protect cells from damage in disease model

Study into how possible treatment affects mitochondria, oxidative stress in cells

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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An illustration of mitochondria.

Treatment with interferon gamma (IFN-gamma), an immune signaling molecule, helped to protect against damage in a cellular model of Friedreich’s ataxia (FA), a study reports.

Although IFN-gamma failed to show clear benefits in clinical trials, these new findings “could help in the design of better therapeutic schedules and shed light on novel therapeutic targets for [FA],” its researchers said.

The study, “Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells,” was published in the International Journal of Molecular Sciences.

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Higher levels of two key proteins, NrF2 and MnSOD, seen in cells

Friedreich’s ataxia is caused by mutations that lead to a severe reduction in levels of the protein frataxin. This protein’s lack causes problems in the workings of mitochondria, the cellular structures that are needed to make energy. The disease is also characterized by increased oxidative stress, a type of cell damage that’s thought to result from an impairment of the body’s antioxidant defenses.

IFN-gamma is a naturally occurring immune signaling molecule, involved in immune reactions and in the iron metabolism that is problematic in patients. Treatment with IFN-gamma has shown promising effects in preclinical studies and in people with FA. IFN-gamma was being developed as a potential disease treatment by Horizon Pharma, but the program was discontinued following disappointing results in a Phase 3 clinical trial.

Scientists in Italy conducted a series of studies in cellular models, including fibroblasts — a type of connective tissue cell — derived from people with FA, with the goal of better characterizing the effects of IFN-gamma at the molecular level.

“A detailed mechanistic understanding of the pathway(s) targeted by this treatment in [FA] cells remains to be elucidated,” they wrote.

Analyses showed that IFN-gamma treatment led to an increase in levels of NrF2, a protein that promotes mitochondrial function and boosts antioxidant responses. Of note, Friedreich ataxia’s first approved therapy, Skyclarys (omaveloxolone), is thought to work mainly by activating NrF2.

Use of IFN-gamma also led to higher levels of MnSOD, a protein that helps to protect cells against oxidative stress. The researchers noted that the increase in MnSOD occurred within a few hours of IFN-gamma treatment, whereas an increase in NrF2 occurred more slowly, suggesting that IFN-gamma’s effect on these two proteins may be through different molecular pathways.

In further experiments, treatment with IFN-gamma helped to protect FA cells from oxidative stress, reducing the cell death caused by hydrogen peroxide.

“Collectively, our data indicate that early pathways arising from IFN-[gamma] stimulation contribute to potentiate cytoprotective [cell-protecting] and antioxidant activities in [FA] cells,” the researchers concluded.

A better understanding of “the synergic action between early and late molecular players” could help open the door to new therapy approaches for this disease, they added.