Tuesday, July 4, 2017

TSRI scientists shed light on molecular workings of MS drug

Image result for dimethyl fumarate
In continuation of my update on Tecfidera

A study by scientists at The Scripps Research Institute (TSRI) has helped to de-mystify the molecular workings of the multiple sclerosis (MS) drug Tecfidera®. The drug is the most widely prescribed pill-based therapy for MS, but its biological mechanism remains mysterious.

Using a new TSRI technology that can quickly reveal a drug's protein targets, the scientists showed that Tecfidera® interacts with multiple T cell proteins, in some cases inhibiting their activity, and helping to suppress the T cell activation that is a key feature of MS flare-ups.

"This new technology has given us insights into the therapeutic modulation of the immune system that we could not have obtained with standard approaches," said co-senior author John R. Teijaro, an assistant professor at TSRI.

The study was reported recently in Science Signaling.
Treatment for an Autoimmune Disease

MS is an autoimmune disease of the brain featuring damage to nerve fibers and producing a range of symptoms, including tingling in the extremities, muscle weakness, muscle spasms, visual problems and mood instability. About 400,000 people in the United States and about 2.5 million worldwide have MS, mostly in a form with intermittent flare-ups of symptoms—which can start to worsen inexorably.

Two large clinical trials published in 2012 found that Tecfidera® is almost twice as effective as an older standard MS drug at reducing the rate of flare-ups. It also appears to slow the disease's progression. But how the drug works has never been clear.

Despite its recent (2013) US Food and Drug Administration approval for MS, the drug is neither new nor high-tech. It is a relatively simple organic compound, dimethyl fumarate (DMF), that has been in the biomedical literature for decades. It was once used in Europe to prevent mold growth in sofas during storage and shipping, although the European Union banned it from consumer products in 2009 after it was linked to severe allergic skin reactions. It has proved more useful as a pharmaceutical: since the 1990s it has been an effective treatment—as the main ingredient in the drug Fumaderm®—for the autoimmune skin disease psoriasis. Success against psoriasis led to its investigation as a potential MS drug.

Until recently, the leading theory was that DMF works against MS primarily by unleashing the activity of a protein called Nrf2, which helps protect the brain from autoimmune damage by marshaling a powerful anti-oxidant response and which may also reduce immune system activation. Studies published in the past year have suggested, however, that DMF works principally by reducing immune system activity and does so independently of Nrf2. In recent years, there have also have been several reports among patients taking Fumaderm® or Tecfidera® of a potentially fatal viral brain infection called progressive multifocal leukoencephalopathy, which normally occurs only in people whose immune systems have been seriously weakened.




TSRI scientists shed light on molecular workings of MS drug: A study by scientists at The Scripps Research Institute has helped to de-mystify the molecular workings of the multiple sclerosis (MS) drug Tecfidera. The drug is the most widely prescribed pill-based therapy for MS, but its biological mechanism remains mysterious.

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