Study Sheds Light on How Tecfidera Kills Immune Cells

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by Marisa Wexler MS |

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The multiple sclerosis (MS) treatment Tecfidera (dimethyl fumarate) triggers immune cell death by interacting with a protein called Keap-1, a new study reveals.

The study, “Wdr1 and cofilin are necessary mediators of immune-cell-specific apoptosis triggered by Tecfidera,” was published in Nature Communications.

Tecfidera is widely approved to treat relapsing types of MS. The name-brand medicine is marketed by Biogen; generic forms also are available. Tecfidera is thought to work broadly by reducing the inflammatory immune attack that causes MS, but the details of its mechanism are poorly understood.

The active agent in Tecfidera is dimethyl fumarate, which is a kind of molecule called a reactive electrophile. These types of molecules seek to bind to other specific molecules that have a free electron pair.

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Studying how reactive electrophiles work has been difficult, in part, because these molecules often interact with many different substances in the body, which can make it complicated to tease out which interactions are needed for a given effect. For example, Tecfidera is known to interact with the protein Keap-1, but it’s not clear whether these interactions are necessary or sufficient for the therapy’s effectiveness in MS.

Now, an international team of researchers used a novel technique called Z-REX to interrogate how Tecfidera interacts with the Keap-1 protein.

The team previously had developed a technique called targetable reactive electrophiles and oxidants, or T-REX, which basically allowed them to study in detail the interaction between a given electrophile and a protein of interest in living cells. In Z-REX, this system was modified to allow similar studies in zebrafish.

“Our experimental approaches offer a unique means to specifically mimic drug action in specific cells and afford a testable model for further investigations,” the team wrote.

Through a battery of experiments, the researchers demonstrated that when Tecfidera interacted with the Keap-1 protein it triggered apoptosis — a form of programmed cell death — in macrophages and neutrophils, which are two types of immune cell thought to contribute to the inflammatory attack that drives MS.

Preventing the fish from making Keap-1, however, eliminated all the effects of Tecfidera on macrophages and neutrophils, whose levels remained similar to those of control animals.

“These data present evidence that Keap1 is a sufficient target of the drug Tecfidera, able to quantitatively account for the gamut of the drug’s apoptotic effects on macrophages and neutrophils,” the team wrote, noting “these data cannot absolutely rule out other targets of the drug.”

Further experiments revealed that this Keap-1-mediated cell death was dependent on molecular signaling from the proteins Wdr1 and cofilin.

They also showed that this type of cell death required the apoptosis-regulating proteins Caspase-3 and Bax, but was independent of another well-established regulator of apoptosis called Nrf2.

“We discovered necessary protein players triggered into action as a result of Keap1-modification by the active electrophiles,” providing additional details on the mechanism of action of Tecfidera, the team concluded.

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