glutaminase and Celiac-Disease

The enzyme transglutaminase 2 (TG2) plays a key role in celiac disease (CeD) pathogenesis. Active TG2 is located mainly extracellularly in the lamina propria but also in the villous enterocytes of the duodenum. The TG2 inhibitor ZED1227 is a promising drug candidate for treating CeD and is designed to block the TG2-catalyzed deamidation and crosslinking of gliadin peptides. Our aim was to study the accumulation of ZED1227 after oral administration of the drug. We studied duodenal biopsies derived from a phase 2a clinical drug trial using an antibody that detects ZED1227 when bound to the catalytic center of TG2. Human epithelial organoids were studied in vitro for the effect of ZED1227 on the activity of TG2 using the 5-biotin-pentylamine assay. The ZED1227-TG2 complex was found mainly in the villous enterocytes in post-treatment biopsies. The signal of ZED1227-TG2 was strongest in the luminal epithelial brush border, while the intensity of the signal in the lamina propria was only ~20% of that in the villous enterocytes. No signal specific to ZED1227 could be detected in pretreatment biopsies or in biopsies from patients randomized to the placebo treatment arm. ZED1227-TG2 staining co-localized with total TG2 and native and deamidated gliadin peptides on the enterocyte luminal surface. Inhibition of TG2 activity by ZED1227 was demonstrated in epithelial organoids. Our findings suggest that active TG2 is present at the luminal side of the villous epithelium and that inhibition of TG2 activity by ZED1227 occurs already there before gliadin peptides enter the lamina propria.

Topics: Celiac Disease; Enterocytes; Gliadin; Glutens; Humans; Peptides; Protein Glutamine gamma Glutamyltransferase 2; Transglutaminases

In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to mucosal injury. Inhibition of transglutaminase 2 is a potential treatment for celiac disease.. In a proof-of-concept trial, we assessed the efficacy and safety of a 6-week treatment with ZED1227, a selective oral transglutaminase 2 inhibitor, at three dose levels as compared with placebo, in adults with well-controlled celiac disease who underwent a daily gluten challenge. The primary end point was the attenuation of gluten-induced mucosal damage, as measured by the ratio of villus height to crypt depth. Secondary end points included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score (for assessment of health-related quality of life).. Of the 41 patients assigned to the 10-mg ZED1227 group, the 41 assigned to the 50-mg group, the 41 assigned to the 100-mg group, and the 40 assigned to the placebo group, 35, 39, 38, and 30 patients, respectively, had adequate duodenal-biopsy samples for the assessment of the primary end point. Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P = 0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001). The estimated differences from placebo in the change in intraepithelial lymphocyte density were -2.7 cells per 100 epithelial cells (95% CI, -7.6 to 2.2) in the 10-mg group, -4.2 cells per 100 epithelial cells (95% CI, -8.9 to 0.6) in the 50-mg group, and -9.6 cells per 100 epithelial cells (95% CI, -14.4 to -4.8) in the 100-mg group. Use of the 100-mg dose may have improved symptom and quality-of-life scores. The most common adverse events, the incidences of which were similar across all groups, were headache, nausea, diarrhea, vomiting, and abdominal pain. Rash developed in 3 of 40 patients (8%) in the 100-mg group.. In this preliminary trial, treatment with ZED1227 attenuated gluten-induced duodenal mucosal damage in patients with celiac disease. (Funded by Dr. Falk Pharma; CEC-3 EudraCT number, 2017-002241-30.).

Topics: Administration, Oral; Adult; Celiac Disease; Dose-Response Relationship, Drug; Double-Blind Method; Duodenum; Female; Glutens; GTP-Binding Proteins; Humans; Imidazoles; Intestinal Mucosa; Lymphocyte Count; Male; Middle Aged; Proof of Concept Study; Protein Glutamine gamma Glutamyltransferase 2; Pyridines; Quality of Life; Severity of Illness Index; Transglutaminases

ZED1227 is a small molecule tissue transglutaminase (TG2) inhibitor. The compound selectively binds to the active state of TG2, forming a stable covalent bond with the cysteine in its catalytic center. The molecule was designed for the treatment of celiac disease. Celiac disease is an autoimmune-mediated chronic inflammatory condition of the small intestine affecting about 1-2% of people in Caucasian populations. The autoimmune disease is triggered by dietary gluten. Consumption of staple foods containing wheat, barley, or rye leads to destruction of the small intestinal mucosa in genetically susceptible individuals, and this is accompanied by the generation of characteristic TG2 autoantibodies. TG2 plays a causative role in the pathogenesis of celiac disease. Upon activation by Ca

Topics: Celiac Disease; Gliadin; Glutens; GTP-Binding Proteins; Humans; Imidazoles; Peptides; Protein Glutamine gamma Glutamyltransferase 2; Pyridines; Transglutaminases

Histological examination of small bowel biopsies is normally the gold standard for the diagnosis of celiac disease (CD). The objective of this study was to investigate whether the rate of decreases in elevated plasma IgA tissue transglutaminase antibody (IgA-tTG) and/or IgG deamidated gliadin peptides antibody (IgG - DGP) concentrations could be used as a confirming test for CD in children on a gluten-free diet (GFD) when biopsy was omitted in the diagnostic process.. In this retrospective study we compared children (≤18 years old) with a CD-confirming biopsy (n = 16) to children without a biopsy (n = 18). After initiation of GFD the antibody half-life (the time (T½) when the antibody concentration is 50% decreased) was determined in all children.. Children with a biopsy (IgA-tTG, T½ = 1.9 months; IgG - DGP, T½ = 2.2 months) and children without a biopsy (IgA-tTG, T½ = 1.6 months; IgG - DGP, T½ = 2.7 months) had comparable T½ (mean) results (p < 0.05) supporting that all children had the CD diagnosis.. When biopsy was omitted a rapid rate of decrease in CD antibody concentrations confirmed the CD diagnosis in children on GFD. The half-lives (T½) of IgA-tTG were less than 2 months in CD children.

Topics: Adolescent; Autoantibodies; Celiac Disease; Child; Child, Preschool; Female; Glutaminase; Half-Life; Humans; Immunoglobulin A; Infant; Male; Treatment Outcome

Blood donor screening can help predict prevalence of coeliac disease in population.. Between December 2010 and June 2011, healthy blood donors were screened using anti-tissue glutaminase antibodies. Those positive underwent duodenoscopy. Their age, gender, body mass index and haemoglobin and histological changes were recorded.. Of the 1610 blood donors screened, 1581 (98.2%) were males. The mean age of donors was 31.51 ± 9.66 years and the mean body mass index was 22.12 ± 4.24 kg/m(2). Nine (0.56%) men were seropositive. Endoscopic features included reduced fold height (9), scalloping (8), grooving (7) and mosaic mucosal pattern (3). Eight had Marsh IIIa changes whilst one had IIIb change. The prevalence of coeliac disease was 1:179 (0.56%, 95% confidence interval 1/366-1/91, 0.27-1.1%). None of the 9 patients had any symptoms. Their mean haemoglobin and body-mass index was similar to rest of the cohort.. The prevalence of coeliac disease amongst apparently healthy blood donors was 1:179 (0.56%).

Topics: Adult; Antibodies; Blood Donors; Celiac Disease; Duodenum; Endoscopy, Gastrointestinal; Female; Glutaminase; Humans; India; Male; Mass Screening; Middle Aged; Prevalence; Young Adult

Dermatitis herpetiformis is associated with celiac disease. IgA antibodies to endomysium are considered as sensitive and specific markers for celiac disease. Recently, tissue transglutaminase was identified as the antigen of anti-endomysium antibodies. Moreover, serum levels of IgA antibodies to tissue transglutaminase were found to correlate with titers of IgA antibodies to endomysium in patients with both celiac disease and dermatitis herpetiformis. These findings confirm the close pathogenic relation between the two diseases. The determination of serum levels of antibodies to tissue transglutaminase may be a tool that can be routinely used for the diagnosis of dermatitis herpetiformis in the future.

Topics: Autoantibodies; Celiac Disease; Dermatitis Herpetiformis; Glutaminase; Humans; Immunoglobulin A; Sensitivity and Specificity

Topics: Celiac Disease; Diet Therapy; Glutaminase; Glutamine; Glutens; Humans; Intestines; Liver; Peptide Hydrolases; Peptides; Plant Proteins; Triticum

Topics: Adult; Biopsy; Celiac Disease; Deficiency Diseases; Diet Therapy; Dietary Proteins; Glutaminase; Glutens; Humans; Intestine, Small; Jejunum; Male