New study demonstrates efficacy of promising celiac disease drug at the molecular level

A recent study conducted by researchers at the University of Tampere tested whether a transglutaminase 2 inhibitor could be an effective drug for treating celiac disease. Previous tissue studies have shown that the transglutaminase 2 inhibitor ZED1227 prevents intestinal damage caused by gluten.

The results of a new study, based on the analysis of the molecular activity of more than 10,000 genes, provide compelling evidence that the first successful drug to treat celiac disease could be developed.

The study was published in the journal Nature Immunology. The publication is part of doctoral student Valerija Dotsenko's dissertation, which she will defend at the Faculty of Medicine and Health Technology at the University of Tampere in August.

Consumption of gluten-containing grains such as wheat, barley and rye causes an abnormal immune response in the small intestine and the development of celiac disease in 2% of the population.

There is currently no drug therapy and the only available treatment is a lifelong strict gluten-free diet. However, symptoms and intestinal damage caused by hidden gluten can occur even in patients who strictly follow the diet.

"Blood tests for antibodies and traditional tissue tests do not always reflect the true state of the intestinal mucosa," says Associate Professor Keijo Viiri. "Our previous studies have shown that even if intestinal tissue appears healthy, it may have molecular 'scars' and, for example, the expression of genes responsible for the absorption of vitamins and micronutrients may be disrupted. This probably explains the frequently observed micronutrient deficiencies in patients with coeliac disease despite a gluten-free diet."

A previous tissue study led by Professor Emeritus Markku Maki from the University of Tampere showed that the transglutaminase 2 inhibitor ZED1227 prevents gluten-induced intestinal damage in patients with celiac disease. However, its mechanisms of action are not yet fully understood.

A new international study led by Tampere University analysed the molecular mechanisms to determine whether ZED1227 is a potential drug candidate for the treatment of celiac disease.

The study assessed the efficacy and molecular mechanisms of action of ZED1227 by analyzing intestinal biopsies collected from patients with celiac disease. Biopsies were taken after a long-term gluten-free diet and again after six weeks of gluten exposure, during which patients ingested 3 grams of gluten per day. At the same time, some patients took a daily dose of 100 milligrams of ZED1227, while others took a placebo.

"By measuring gene activity, we found that oral administration of ZED1227 effectively prevented damage and inflammation of the intestinal mucosa caused by gluten. In the group taking the drug, the activity of genes responsible for the absorption of nutrients and micronutrients also returned to levels before gluten exposure," says Viiri.

In the intestines of patients with celiac disease, inflammation and mucosal damage occur through several cellular and molecular events when gluten binds to human leukocyte antigen (HLA) molecules. However, gluten can only bind to HLA after the enzyme transglutaminase 2 in the small intestine first chemically modifies, or deaminates, the gluten structure. The efficacy of ZED1227 is based on its ability to prevent deamination.

"It is too early to say that ZED1227 will be the drug of the future for celiac disease, eliminating the need for a gluten-free diet. However, it is a strong drug candidate that could potentially be used in combination with a gluten-free diet. If or when ZED1227 becomes available, it would be useful to use it as part of personalized medicine, especially for patients with celiac disease and a high-risk HLA genotype," says Veery.