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Potential drug to treat celiac disease prevents damage caused by gluten in recent study of molecular action

July 9, 2024

Researchers look at what’s happening inside cells in latest study of ZED1227

By Amy Ratner, director of scientific affairs

A new study that analyzed the activity of more than 10,000 genes found that a drug being investigated to treat celiac disease prevented intestinal damage caused by gluten.

The research focused on the molecular mechanism of ZED1227, a treatment designed to block transglutaminase 2 (TTG), an enzyme that reacts with fragments of gluten. This reaction makes the fragments more recognizable to the cells that cause destruction of the nutrient-absorbing finger-like projections in the intestine of those who have celiac disease.

Looking deeper with molecular study

Understanding of molecular mechanisms is important to scientists because it can help identify and develop drugs to block or reverse a molecular change without affecting healthy processes in the body.

Molecular study gives deeper information than traditional studies of biopsies of intestinal tissue about how a drug works, said Markku Maki, MD, professor emeritus, University of Tampere, Finland. This kind of study tells you what is happening inside cells and gives a fingerprint of cell identity. The result is more complete information than comes from viewing cells through a microscope, according to Maki, a study author.

While earlier clinical trials showed that ZED1227 prevented intestinal damage, the drug’s mechanism of action was not fully understood.

How the study was done

The latest research led by scientists from Tampere University and published in the journal Nature Immunology further analyzed intestinal biopsies taken from 58 of the celiac disease patients from the earlier trial who had received the highest dose of ZED1227. An initial biopsy was taken at the start of the study, when participants had been on a long-term gluten-free diet, and another was taken after six weeks of a gluten challenge.

Study participants were given three grams of gluten per day for six weeks. Thirty four received 100 milligrams of ZED1227 daily and 24 got a placebo, which did not contain the drug.

RNA analysis

RNA molecules taken from the biopsy samples were analyzed. In samples from study participants who received the drug, changes in gene expression caused by gluten were eliminated, according to the study. These changes were not present in study participants who received the placebo. This evaluation of RNA, also called transcriptomics, provided molecular level evidence that inhibiting TTG is an effective strategy for treating celiac disease, the study found.

“By measuring gene activity, we found that orally ingested ZED1227 effectively prevented gluten-induced intestinal mucosal damage and inflammation,” study author Keijo Viiri, PhD, of Tampere University, said in a press release. The earlier clinical trial that evaluated tissue from biopsies found a similar response to the drug.

TTG changes structure of gluten

In those who have celiac disease, inflammation and intestinal damage occurs when gluten binds to human leukocyte antigen (HLA) molecules. This can only happen when TTG chemically changes the structure of gluten, a process called deamidation.

Deamidation leads to a strong anti-gluten, T-cell response and the secretion of cytokines, which are small proteins released by cells that have a specific effect on the interactions and communications between cells. The effectiveness of ZED1227 is based on its ability to prevent deamidation, the study says.

By inhibiting the deamidation activity of TTG, all immunological changes in celiac disease can be prevented, the study found.

Why vitamins levels may be low even on the gluten-free diet

The study also suggests that the activity of genes responsible for the absorbing vitamins and nutrients explains why those with celiac disease sometimes have low vitamin and nutrient levels even on the gluten-free diet.

“Blood antibody tests and traditional tissue tests do not necessarily tell the whole truth about the condition of the intestinal mucosa,” he said, noting that previous studies have shown that even though the intestinal tissue may look healthy, it can still have a molecular “scar.”

“For example, the expression of genes promoting the absorption of vitamins and trace elements may be deficient. This probably explains the often-observed deficiencies of trace elements in celiac patients despite a gluten-free diet,” he said.

Inadvertent gluten ingestion often leads to ongoing damage to the intestine, leading even those who follow the gluten-free diet to have nutrient imbalances and deficiencies. Despite having a normal intestinal tissue, individuals with celiac disease on a gluten-free diet differ from those who do not have celiac disease on the molecular level, the study says. This argues for a treatment in addition to the gluten-free diet.

For those who received ZED1227, the activity of the genes responsible for the absorption of nutrients and trace elements also returned to the pre-gluten exposure level, Viiri said in the press release.


The study also used organoids, which are tiny three-dimensional mini organs grown in a petri dish from the intestinal cells, to investigate the role a cytokine that causes inflammation plays in celiac disease. Researchers treated organoids with the cytokine interferon gamma to see what kind of molecular level changes occurred. Evidence from the organoids was compared to evidence from patients and showed that nearly half of the changes caused by gluten are due to a response to this cytokine.

Additionally, the study showed that this cytokine response was stronger in those with celiac disease who have two copies of the genes associated with celiac disease, one from each parent. These celiac disease patients might need a higher dose of ZED1227.

Future directions

The study results support the theory that celiac disease could be used as a model for treatment of other autoimmune diseases, for example rheumatoid arthritis, according to the authors.

Additionally, the study suggests that it is possible to measure intestinal tissue damage objectively and quantitatively in celiac disease research and clinical trials for new drugs.

Tampere researchers plan to test whether molecular study is a sensitive tool for determining the benefits of ZED1227 in real life situations in which only small amounts of inadvertent gluten trigger celiac disease symptoms.

“We are still at an early phase of clinical drug development,” the authors wrote. “The message for patients is that first-line therapies will potentially be in addition to the gluten-free diet, and ZED127 is a strong investigational medical product candidate.”

You can read more about the study here.


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