The Oral Transglutaminase 2 Inhibitor ZED1227 Accumulates in the Villous Enterocytes in Celiac Disease Patients during Gluten Challenge and Drug Treatment.

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.

Emerging drugs for celiac disease.

INTRODUCTION: Celiac disease is an immune-mediated gluten-dependent disorder, primarily affecting the small intestine in genetically predisposed individuals. The disorder has a very heterogeneous clinical and histopathological spectrum. Current treatment with a gluten-free diet is very effective, but the diet is difficult to maintain and remains costly. AREAS COVERED: Alternatives to the gluten-free diet have been proposed to either replace this current treatment, or at least, to supplement use of the gluten-free diet. Studies in the published English language literature relevant to this review were examined for this report. EXPERT OPINION: Most recent published double-blind, placebo-controlled clinical trials have focused on an orally administered recombinant glutenase (ALV003) showing significant but limited benefit to celiac disease patients already compliant with a gluten-free diet. Other studies have addressed other immune mechanisms that may play a role in its pathogenesis and have not been so positive. Added investigations, particularly over the long-term, in other larger and more heterogeneous populations are needed.

Doença celíaca / Celiac disease

A doença celíaca (DC) é uma enteropatia caracterizada pela intolerância permanente ao glúten desencadeada por mecanismos autoimunes nos indivíduos geneticamente predispostos. A DC com seu quadro clínico típico e principalmente atípico tem se mostrado mais frequente do que se imaginava. Seu diagnóstico é baseado em suspeita clínica, exames sorológicos e biópsia intestinal. Devido à evolução dos marcadoressorológicos e revisão dos critérios diagnósticos, discute-se sobre a real necessidade da realização da biópsia intestinal em casos selecionados. O tratamento da DC continua sendo a dieta isenta de glúten.

Celiac disease (CD) is an enteropathy characterized by permanent intolerance to gluten triggered by autoimmune mechanisms in genetically predisposed individuals. The frequency of CD, with its typical clinical condition and mainly atypical, has been higher than expected. Its diagnosis is based on clinical suspicion, serologic tests, and intestinal biopsy. The evolution of the knowledge about serological markers and revision of thediagnostic criteria prompts questions about the real need of intestinal biopsy in selected cases. The treatment of CD remains the gluten-free diet.