Bromelain-loaded nanocomposites decrease inflammatory and cytotoxicity effects of gliadin on Caco-2 cells and peripheral blood mononuclear cells of celiac patients.

Enzyme therapy can be an appropriate treatment option for celiac disease (CeD). Here, we developed Bromelain-Loaded Nanocomposites (BLNCs) to improve the stability and retention of bromelain enzyme activity. After the characterization of BLNCs, the cytotoxicity of BLNCs was determined on the Caco-2 cell line. The effect of BLNCs on gliadin degradation and the production of pro-inflammatory cytokines and anti-inflammatory molecules in peripheral blood mononuclear cells (PBMCs) obtained from celiac patients were assessed. Furthermore, the expression of CXCR3 and CCR5 genes was measured in CaCo-2 cells treated with gliadin, gliadin-digested with BLNCs, and bromelain. Our study demonstrated that the Bromelain entrapment efficiency in these nanoparticles was acceptable, and BLNCs have no toxic effect on cells. SDS-PAGE confirmed the digestion effect of bromelain released from nanocomposites. When Caco-2 cells were treated with gliadin digested by free bromelain and BLNCs, the expression of CXCR3 and CCR5 genes was significantly decreased. PBMCs of celiac patients treated with Bromelain and BLNCs decreased inflammatory cytokines (IL-1ß, IL-6, TNF-α, and IFN-γ) production compared to untreated PBMCs. This treatment also increased IL-10 and CTLA-4 in PBMCs of CeD patients. According to the promising results of this study, we can hope for the therapeutic potential of BLNCs for CeD.

Zinc Deficiency and Therapeutic Value of Zinc Supplementation in Pediatric Gastrointestinal Diseases.

The benefits of zinc in treating certain gastrointestinal (GI) diseases have been recognized for over two decades. This review aims to explore zinc deficiency (ZD) and the potential therapeutic value and safety of zinc supplementation in pediatric GI diseases. A systematic review of published articles on ZD and zinc as adjuvant treatments for GI diseases was conducted using various databases. Children with inflammatory bowel disease (IBD), celiac disease, and those receiving long-term proton pump inhibitor treatments are particularly susceptible to ZD. ZD in children with celiac disease and IBD is attributed to insufficient intake, reduced absorption, and increased intestinal loss as a result of the inflammatory process. Zinc plays a crucial role in maintaining the integrity of the gastric mucosa and exerts a gastroprotective action against gastric lesions. Although considerable evidence supports the use of zinc as adjuvant therapy for certain GI diseases in adults, its use is unspecified in children except for infectious diarrhea. Current evidence suggests that zinc supplementation with well-documented dosages helps reduce the duration of diarrhea in children with acute or persistent diarrhea, while there are no specific guidelines for zinc supplementation in children with IBD and celiac disease. Zinc supplementation appears to be beneficial in peptic ulcer disease or gastroesophageal reflux disease. The available evidence highlights the need for intervention programs to enhance zinc status and reduce the morbidity of certain GI diseases in children.

Tofacitinib for celiac disease and microscopic colitis: killing two birds with one stone.

Microscopic colitis is a chronic inflammatory condition of the colon. Firstline treatment consists of budesonide, with the consideration of biological agents in refractory cases. Celiac disease is a chronic immune mediated and gluten-induced enteropathy, with treatment consisting of a gluten-free diet. There is an association between microscopic colitis and instead of xand celiac disease, especially in refractory cases they can coincide. In this manuscript, we report for the first time the efficacy of tofacitinib, a pan Janus kinase inhibitor, in the treatment of concomitant microscopic colitis and celiac disease, resulting in persistent clinical and histological remission.

Safety and tolerability of KAN-101, a liver-targeted immune tolerance therapy, in patients with coeliac disease (ACeD): a phase 1 trial.

BACKGROUND: Coeliac disease management is limited to strict adherence to a gluten-free diet with no approved therapies. This first-in-human phase 1 study evaluated the safety and tolerability of KAN-101, a liver-targeting glycosylation signature conjugated to a deaminated gliadin peptide designed to induce immune tolerance to gliadin. METHODS: Adults (aged 18-70 years) with biopsy-confirmed, HLA-DQ2.5 genotype coeliac disease were enrolled from clinical research units and hospitals in the USA. Part A of the trial was an open-label, single ascending dose study of intravenous KAN-101 using sentinel dosing in evaluation of the following cohorts: 0·15 mg/kg, 0·3 mg/kg, 0·6 mg/kg, 1·2 mg/kg, and 1·5 mg/kg. Following safety monitoring committee review of the 0·3 mg/kg dose level in part A, part B was initiated as a randomised, placebo-controlled, multiple ascending dose study. In part B, interactive response technology was used to randomly assign (5:1) patients to receive intravenous KAN-101 (0·15 mg/kg, 0·3 mg/kg, or 0·6 mg/kg) or placebo following a 1:1 assignment of the first two eligible patients in each cohort for sentinel dosing. Patients in part B received three administrations of KAN-101 or placebo followed by a 3-day oral gluten challenge (9 g per day) 1 week after completing dosing. Study personnel and patients were masked to treatment assignments in part B, and not in part A. The primary endpoint was the incidence and severity of adverse events with escalating doses of KAN-101, assessed in all patients who received any amount of study drug based on dose level received. The secondary endpoint was assessment of plasma concentrations and pharmacokinetic parameters of KAN-101 following single and multiple doses, assessed in all patients who received at least one dose and had one or more values for drug concentration. This study is registered with ClinicalTrials.gov, NCT04248855, and is completed. FINDINGS: Between Feb 7, 2020, and Oct 8, 2021, 41 patients were enrolled at ten US sites. 14 patients were assigned to part A (four 0·15 mg/kg, three 0·3 mg/kg, three 0·6 mg/kg, three 1·2 mg/kg, one 1·5 mg/kg) and 27 patients to part B (six 0·15 mg/kg with two placebo, seven 0·3 mg/kg with two placebo, and eight 0·6 mg/kg with two placebo). Treatment-related adverse events were reported in 11 (79%) of 14 patients in part A and 18 (67%) of 27 in part B (placebo two [33%] of six patients; KAN-101 16 [76%] of 21 patients), were grade 2 or lower, and were mild to moderate in severity. The most commonly observed adverse events were nausea, diarrhoea, abdominal pain, and vomiting, consistent with symptoms had by patients with coeliac disease on gluten ingestion. No grade 3-4 adverse events, serious adverse events, dose-limiting toxicities, or deaths occurred. Pharmacokinetic analyses showed KAN-101 was cleared from systemic circulation within roughly 6 h with a geometric mean half-life of 3·72 min (CV% 6·5%) to 31·72 min (83·7%), and no accumulation with repeated dosing. INTERPRETATION: KAN-101 has an acceptable safety profile in patients with coeliac disease with no dose-limiting toxicities and no maximum tolerated dose was observed. Rapid systemic clearance of KAN-101 was observed and no accumulation on repeated dosing. A future study will evaluate the safety and efficacy, including biomarker responses with a gluten challenge, of KAN-101 at doses 0·6 mg/kg and greater in patients with coeliac disease. FUNDING: Kanyos Bio.

Inhibition of Transglutaminase 2 as a Therapeutic Strategy in Celiac Disease-In Vitro Studies in Intestinal Cells and Duodenal Biopsies.

Enzymatic modification of gliadin peptides by human transglutaminase 2 (TG2) is a key mechanism in the pathogenesis of celiac disease (CD) and represents a potential therapeutic target. Recently, we have identified the small oxidative molecule PX-12 as an effective inhibitor of TG2 in vitro. In this study, we further investigated the effect of PX-12 and the established active-site directed inhibitor ERW1041 on TG2 activity and epithelial transport of gliadin peptides. We analyzed TG2 activity using immobilized TG2, Caco-2 cell lysates, confluent Caco-2 cell monolayers and duodenal biopsies from CD patients. TG2-mediated cross-linking of pepsin-/trypsin-digested gliadin (PTG) and 5BP (5-biotinamidopentylamine) was quantified by colorimetry, fluorometry and confocal microscopy. Cell viability was tested with a resazurin-based fluorometric assay. Epithelial transport of promofluor-conjugated gliadin peptides P31-43 and P56-88 was analyzed by fluorometry and confocal microscopy. PX-12 reduced TG2-mediated cross-linking of PTG and was significantly more effective than ERW1041 (10 µM, 15 ± 3 vs. 48 ± 8%, p < 0.001). In addition, PX-12 inhibited TG2 in cell lysates obtained from Caco-2 cells more than ERW1041 (10 µM; 12 ± 7% vs. 45 ± 19%, p < 0.05). Both substances inhibited TG2 comparably in the intestinal lamina propria of duodenal biopsies (100 µM, 25 ± 13% vs. 22 ± 11%). However, PX-12 did not inhibit TG2 in confluent Caco-2 cells, whereas ERW1041 showed a dose-dependent effect. Similarly, epithelial transport of P56-88 was inhibited by ERW1041, but not by PX-12. Cell viability was not negatively affected by either substance at concentrations up to 100 µM. PX-12 did not reduce TG2 activity or gliadin peptide transport in confluent Caco-2 cells. This could be caused by rapid inactivation or degradation of the substance in the Caco-2 cell culture. Still, our in vitro data underline the potential of the oxidative inhibition of TG2. The fact that the TG2-specific inhibitor ERW1041 reduced the epithelial uptake of P56-88 in Caco-2 cells further strengthens the therapeutic potential of TG2 inhibitors in CD.

Efficacy and safety of gluten peptide-based antigen-specific immunotherapy (Nexvax2) in adults with coeliac disease after bolus exposure to gluten (RESET CeD): an interim analysis of a terminated randomised, double-blind, placebo-controlled phase 2 study.

BACKGROUND: A gluten-free diet is insufficient to treat coeliac disease because intestinal injury persists and acute reactions with cytokine release follow gluten exposure. Nexvax2 is a specific immunotherapy using immunodominant peptides recognised by gluten-specific CD4+ T cells that might modify gluten-induced disease in coeliac disease. We aimed to assess the effects of Nexvax2 on gluten-induced symptoms and immune activation in patients with coeliac disease. METHODS: This was a randomised, double-blind, placebo-controlled phase 2 trial done at 41 sites (29 community, one secondary, and 11 tertiary centres) in the USA, Australia, and New Zealand. Patients with coeliac disease aged 18-70 years who had excluded gluten for at least 1 year, were HLA-DQ2.5 positive, and had a worsening of symptoms after an unmasked 10 g vital gluten challenge were eligible for inclusion. Patients were stratified by HLA-DQ2.5 status (HLA-DQ2.5 non-homozygous vs homozygous). Patients who were non-homozygous were centrally (ICON; Dublin, Ireland) randomly assigned (1:1) to receive subcutaneous Nexvax2 (non-homozygous Nexvax2 group) or saline (0·9% sodium chloride; non-homozygous placebo group) twice a week escalating from 1 µg to 750 µg during the first 5 weeks followed by 11 weeks of maintenance therapy at 900 µg per dose. The exploratory homozygous group was centrally randomly assigned (2:1) to receive Nexvax2 (homozygous Nexvax2 group) or placebo (homozygous placebo group); patients who were homozygous received the same dosage as those who were non-homozygous. The primary endpoint was change in coeliac disease patient reported outcomes (total gastrointestinal domain) from pretreatment baseline to the day of masked bolus 10 g vital gluten challenge given in week 14 analysed in the non-homozygous intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT03644069. FINDINGS: Between Sept 21, 2018, and April 24, 2019, 383 volunteers were screened for inclusion, of whom 179 (47%; 133 [74%] women, 46 [26%] men; median age 41 years [IQR 33-55]) were randomly assigned. One (1%) of 179 patients was excluded from analysis due to misassignment of genotype. The non-homozygous Nexvax2 group included 76 patients, the non-homozygous placebo group included 78 patients, the homozygous Nexvax2 group included 16 patients, and the homozygous placebo group included eight patients. The study was discontinued after planned interim analysis of 66 patients who were non-homozygous. We report an unmasked post-hoc analysis of all available data for the primary endpoint and secondary symptom-based endpoints combining data from 67 (66 were assessed in the planned interim analysis for the primary endpoint). Mean change from baseline to day of first masked gluten challenge in total gastrointestinal score for the non-homozygous Nexvax2 group was 2·86 (SD 2·28) compared with 2·63 (2·07) for the non-homozygous placebo group (p=0·43). Adverse events were similar between all patients who received Nexvax2 and those who received placebo. Serious adverse events were reported in five (3%) of 178 patients (two [2%] of 92 who received Nexvax2 and three [4%] of 82 who received placebo). One patient in the non-homozygous Nexvax2 group had a serious adverse event that occurred during gluten challenge (left-sided mid-back muscle strain with imaging suggestive of partial left kidney infarction). Serious adverse events were reported for three (4%) of 78 patients in the non-homozygous placebo group (one each with exacerbation of asthma and appendicitis, and one who had forehead abscess, conjunctivitis, and folliculitis) and one (1%) patient in the non-homozygous Nexvax2 group developed a pulmonary embolism. The most frequent adverse events in all 92 patients who received Nexvax2 compared with all 86 patients who received placebo were nausea (44 [48%] of 92 patients who received Nexvax2 vs 29 (34%) of 86 patients who received placebo), diarrhoea (32 [35%] vs 25 [29%]), abdominal pain (31 [34%] vs 27 [31%]), headache 32 [35%] vs 20 [23%]), and fatigue (24 [26%] vs 31 [36%]). INTERPRETATION: Nexvax2 did not reduce acute gluten-induced symptoms. Masked bolus vital gluten challenge provides an alternative to extended gluten challenge in efficacy studies for coeliac disease. FUNDING: ImmusanT.

Subclinical Celiac Disease Unmasked by Immune Checkpoint Inhibitor Therapy.

Immune checkpoint inhibitors (ICI) are antibodies that block immune checkpoint proteins from binding with their partner proteins on cancer cells, subsequently allowing cytotoxic T-cell-associated enhancement of antitumor responses. Although ICIs have become the standard of care for various malignancies, their use is often limited by unique immune-related adverse events, including dermatologic, endocrine, inflammatory, hepatic, and gastrointestinal events. Diarrhea and colitis are common lower gastrointestinal tract immune-related adverse events, however, only a few cases have reported the association between celiac disease (CD) and ICIs. We report here a case of a 75-year-old man with new onset CD after exposure to the cytotoxic T-lymphocyte-associated antigen-4 ICI, ipilimumab. Although ICI-induced CD is relatively rare, it is essential to consider it in a genetically susceptible patient undergoing treatment with ICI. Patients with known high susceptibility to CD, such as a family history of CD, or with the ancestry of high celiac penetrance (eg, Northern Europe, North Africa, etc), dermatitis herpetiformis, or chronic bowel symptoms, we feel should have celiac panel testing before initiating ICI therapy.

Intravenous route for folate supplementation in a patient with celiac disease treated by pemetrexed-based chemotherapy for non-small-cell lung cancer.

INTRODUCTION: Oral folic acid supplementation is essential for patients treated with pemetrexed, to prevent the risk of severe hematologic toxicity. In case of intestinal absorption disorder, no recommendations exist for intravenous folic acid supplementation. CASE REPORT: We describe a 74-year-old patient with multimetastatic non-small-cell lung adenocarcinoma, receiving first-line chemotherapy with carboplatin AUC5, pemetrexed 500 mg/m2 and pembrolizumab 200 mg intravenously every 3 weeks. The patient presented neglected celiac disease, resulting in malabsorption syndrome with iron and folic acid deficiency. The question was how to administer folic acid supplementation during the pemetrexed-based chemotherapy. MANAGEMENT AND OUTCOMES: Intravenous injection of 200 mg levoleucovorin on day 1 of cycle 1 of pemetrexed-based chemotherapy was administered and well tolerated. During the second cycle, the levoleucovorin perfusion was not renewed by omission. The patient was hospitalized for 7 days because of febrile aplasia. Piperacillin-tazobactam was started, and then switched to amoxicillin-clavulanate plus ciprofloxacin. After this episode of post-chemotherapy febrile aplasia, it was decided to systematically supplement the patient with intravenous levoleucovorin, with blood folate concentration monitoring at each cycle. At 16 months after start of treatment, the patient was in complete remission, indicating that the immune-chemotherapy was effective, with no further febrile neutropenia. DISCUSSION/CONCLUSION: This case report highlights intravenous levoleucovorin supplementation as an alternative to oral folic acid if needed during pemetrexed-antifolate-based chemotherapy.

Role of Vitamin D in Celiac Disease and Inflammatory Bowel Diseases.

Vitamin D (VD) is a pro-hormone that has long been known as a key regulator of calcium homeostasis and bone health in both children and adults. In recent years, studies have shown that VD may exert many extra-skeletal functions, mainly through a relevant modulation of the innate and adaptive immune system. This has suggested that VD could play a fundamental role in conditioning development, clinical course, and treatment of several autoimmune disorders, including celiac disease (CD) and inflammatory bowel diseases (IBDs). The main aim of this review is to evaluate the relationships between VD, CD, and IBDs. Literature analysis showed a potential impact of VD on CD and IBDs can be reasonably assumed based on the well-documented in vitro and in vivo VD activities on the gastrointestinal tract and the immune system. The evidence that VD can preserve intestinal mucosa from chemical and immunological damage and that VD modulation of the immune system functions can contrast the mechanisms that lead to the intestinal modifications characteristic of gastrointestinal autoimmune diseases has suggested that VD could play a role in controlling both the development and the course of CD and IBDs. Administration of VD in already diagnosed CD and IBD cases has not always significantly modified disease course. However, despite these relevant problems, most of the experts recommend monitoring of VD levels in patients with CD and IBDs and administration of supplements in patients with hypovitaminosis.

Vitamin D in Prevention of Autoimmune Diseases.

Vitamin D is essential for the regulation of the immune system. In recent years, the role of vitamin D in the control of several autoimmune conditions such as inflammatory bowel disease (IBD), celiac disease, type 1 diabetes mellitus (T1DM), and others has been investigated. The aim of this review was to define the level of knowledge on vitamin D's role in these disorders, as well as the preventive and therapeutic role of vitamin D supplementation. Relevant studies published over the last 20 years were identified via a PubMed/Medline (http://www.ncbi.nlm.nih.gov/pubmed/) search using the keywords: vitamin D, autoimmune disease, and prevention. Vitamin D deficiency or impaired function of the enzymes necessary for its activity has been shown to affect the onset and severity of the autoimmune diseases examined. Vitamin D supplementation appears useful in the support therapy of IBD. Its role in celiac disease, autoimmune hepatitis, T1DM, and autoimmune thyroiditis is unclear. In conclusion, further studies are needed to define whether vitamin D is a cause or a result of the most common autoimmune, extra-skeletal diseases, such as IBD. Vitamin D should be provided to all newborns during their first year of life. Afterwards, the vitamin D supplementation regimen should be tailored to the presence of risk factors for vitamin D deficiency and/or specific disease.

Celiaquía y aspectos psicológicos. Abordaje emocional del paciente celíaco. RS III

En esta charla, la nutricionista Camila Guruceaga y la psicóloga social Jaqueline Riquelme, referente del Programa de Celiaquía en Región Sanitaria III, abordan los aspectos psicosociales de la celiaquía, el impacto emocional en el paciente y el necesario abordaje interdisciplinario de éste. Entre los temas desarrollados destacan los tipos de reacciones ante el diagnóstico y las acciones propuestas por el profesional en cada caso, la relevancia del entender al paciente como un ser social, con vivencias y sentimientos, y el impacto del entorno familiar y vincular. Más adelante, reafirman la importancia de asegurar la continuidad del plan alimenticio y el cuidado personal, sin desatender el impacto que sobre éste tenga el contexto. Otros ítems tratados fueron el ASPO y el Covid-19, la seguridad alimentaria, la edad de los pacientes y diferentes formas de abordaje médico y psicosocial, el apoyo familiar. Dentro de las herramientas que deben brindar los profesionales resaltaron la búsqueda de ayuda psicológica. Para finalizar, las especialistas recomendaron entender la enfermedad de la celiaquía desde una mirada integral que implique una forma de trabajo interdisciplinaria y donde, en vez de acompañar al paciente, el profesional de la salud se proponga “acompasar”, “ir a su paso”.

Budesonide and the Gluten Containing Elimination Diet as Treatments for Non-responsive Celiac Disease in Children.

OBJECTIVES: Non-responsive celiac disease (NRCD) is defined as patients having persistent symptoms and enteropathy (Marsh 3 histology) suggestive of active celiac disease (CeD), after following a gluten-free diet (GFD) for at least 12 months. NRCD is suggested to affect 15% of children with CeD but data are limited and there is no research to date describing treatment of children with this condition. The aim of this study was to describe our center's approach to identifying and treating NRCD with budesonide and the Gluten Containing Elimination Diet (GCED). METHODS: We performed a retrospective, single center analysis over a 5-year period of patients with CD less than 18 years of age (inclusive) who underwent treatment for persistent symptoms and enteropathy despite following a GFD. RESULTS: We identified 22 patients with NRCD. Thirteen were treated with the GCED for 3 months with 46% achieving both histological and symptomatic resolution. Nine patients were treated with budesonide (6-9 mg), with 89% achieving both symptomatic and histologic resolution after a median 3-month treatment course. Further, 67% of patients who responded to the GCED and 100% of patients who responded to budesonide remained in remission for at least 6 months following treatment transition back to exclusive GFD. CONCLUSIONS: The GCED and budesonide can provide benefit for NRCD. Most patients with NRCD can return to a GFD after 3 months of treatment.

Novel Drug Therapeutics in Celiac Disease: A Pipeline Review.

Celiac disease (CeD) is a chronic, autoimmune systemic disorder triggered by the ingestion of gluten, a protein found in foods such as wheat, rye, and barley. The only effective treatment for CeD is complete removal of gluten from the diet. A strict gluten-free diet (GFD) results in symptomatic, serologic, and histologic remission in most patients. However, GFD may fail to induce clinical or histologic improvement and some patients may alternatively have difficulty strictly adhering to the GFD for other reasons. Despite this, there are currently no FDA-approved drugs for the treatment of CeD. The complex pathogenic process of CeD is becoming increasingly studied and better understood, enabling the identification of various targets for future therapies. Mechanisms under evaluation include probiotics, digestion of peptides, gluten sensitization, tight junction modulation, deamidation, and immune targets. Multiple investigational drugs are in the pipeline, and several drug candidates have entered late-phase clinical trials. Indeed, current and future studies are needed to target specific etiological mechanisms and provide an alternative to GFD alone. This review provides a broad overview of the various investigative treatment approaches for CeD, summarizing the latest progress in the pipeline.

Celiac disease: New therapies on the horizon.

Celiac Disease (CeD) is a chronic intestinal disease which occurs in 0.7-1.4% of the global population. Since the discovery of gluten as its disease-inducing antigen, CeD patients are treated with a gluten-free diet which is effective but has limitations for certain groups of patients. Accordingly, over the past few years, there is a growing interest in alternative treatment options. This review summarizes emerging pharmacological approaches, including tolerance induction strategies, tissue transglutaminase inhibition, gluten degradation, and inhibition of interleukin (IL)-15.

Molecular and in vivo studies of a glutamate-class prolyl-endopeptidase for coeliac disease therapy.

The digestion of gluten generates toxic peptides, among which a highly immunogenic proline-rich 33-mer from wheat α-gliadin, that trigger coeliac disease. Neprosin from the pitcher plant is a reported prolyl endopeptidase. Here, we produce recombinant neprosin and its mutants, and find that full-length neprosin is a zymogen, which is self-activated at gastric pH by the release of an all-ß pro-domain via a pH-switch mechanism featuring a lysine plug. The catalytic domain is an atypical 7+8-stranded ß-sandwich with an extended active-site cleft containing an unprecedented pair of catalytic glutamates. Neprosin efficiently degrades both gliadin and the 33-mer in vitro under gastric conditions and is reversibly inactivated at pH > 5. Moreover, co-administration of gliadin and the neprosin zymogen at the ratio 500:1 reduces the abundance of the 33-mer in the small intestine of mice by up to 90%. Neprosin therefore founds a family of eukaryotic glutamate endopeptidases that fulfils requisites for a therapeutic glutenase.

Latiglutenase Protects the Mucosa and Attenuates Symptom Severity in Patients With Celiac Disease Exposed to a Gluten Challenge.

BACKGROUND & AIMS: Gluten ingestion in patients with celiac disease can lead to gastrointestinal symptoms and small intestinal mucosal injury. METHODS: This gluten challenge phase 2 trial was double blind and placebo controlled, and it assessed the efficacy and safety of a 1200-mg dose of IMGX003 in patients with celiac disease exposed to 2 g of gluten per day for 6 weeks. The change in the ratio of villus height to crypt depth was the primary endpoint. Secondary endpoints included density of intraepithelial lymphocytes and symptom severity. These endpoints were evaluated by analysis of covariance. Additional endpoints included serology and gluten-immunogenic peptides in urine. RESULTS: Fifty patients were randomized, and 43 patients completed the study (IMGX003, n = 21; placebo, n = 22). The mean change in the ratio of villus height to crypt depth (primary endpoint) for IMGX003 vs placebo was -0.04 vs -0.35 (P = .057). The mean change in the density of intraepithelial lymphocytes (secondary endpoint) for IMGX003 vs placebo was 9.8 vs 24.8 cells/mm epithelium (P = .018). The mean change (worsening) in symptom severity in relative units (secondary endpoint) for IMGX003 vs placebo was 0.22 vs 1.63 (abdominal pain, P = .231), 0.96 vs 3.29 (bloating, P = .204), and 0.02 vs 3.20 (tiredness, P = .113). The 3 × 2-week trend line significance values for these symptoms, respectively, were P = .014, .030, and .002. CONCLUSIONS: IMGX003 reduced gluten-induced intestinal mucosal damage and symptom severity. (ClinicalTrials.gov, Number: NCT03585478).

Remodeling Immune Response in A Celiac Disease Patient Using Herbal Supplementation: A Clinical Case-Study.

Background: Celiac disease (CD) is an autoimmune disorder characterized by abnormal serological response (autoimmune anti-tissue-Transglutaminase antibodies) triggered by gluten ingestion in genetically predisposed individuals. The only available effective management for those patients is a strict gluten-free diet. Aim: To investigate the improvement of CD after completing a traditional herbal supplementation and alternative medicine treatment. Case description, treatment, and results: A 23-year-old female presented with a confirmed CD diagnosis (positive anti-tissue Transglutaminase IgA with infiltration of mixed inflammatory cell detected in small bowel biopsy). After 9 months of alternative treatment with traditional herbal supplementation (Taraxaf®, Ferrolina®, and Indomirol®), the clinical, laboratory, and endoscopy profile tests have shown an overall improvement with negative results for anti-tissue Transglutaminase IgA, and normal small bowel mucosal appearance. She was returned to an ordinary diet containing gluten. Conclusion: A traditional herbal supplementation with specific doses followed by a physician's instruction led to obvious improvement in this CD patient.

Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease.

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 Ca2+, it catalyzes the deamidation of gliadin peptides as well as the crosslinking of gliadin peptides to TG2 itself. These modified biological structures trigger breaking of oral tolerance to gluten, self-tolerance to TG2, and the activation of cytotoxic immune cells in the gut mucosa. Recently, in an exploratory proof-of-concept study, ZED1227 administration clinically validated TG2 as a "druggable" target in celiac disease. Here, we describe the specific features and profiling data of the drug candidate ZED1227. Further, we give an outlook on TG2 inhibition as a therapeutic approach in indications beyond celiac disease.