A Randomized, Double-Blind Study of Larazotide Acetate to Prevent the Activation of Celiac Disease During Gluten Challenge

Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
The American Journal of Gastroenterology (Impact Factor: 10.76). 07/2012; 107(10):1554-62. DOI: 10.1038/ajg.2012.211
Source: PubMed


OBJECTIVES: In patients with celiac disease, enteropathy is caused by the entry of gluten peptides into the lamina propria of the intestine, in which their immunogenicity is potentiated by tissue transglutaminase (tTG) and T-helper type 1–mediated immune responses are triggered. Tight junction disassembly and paracellular permeability are believed to have an important role in the transport of gluten peptides to the lamina propria. Larazotide acetate is a tight-junction regulator peptide that, in vitro, prevents the opening of intestinal epithelial tight junctions. The aim of this study was to evaluate the efficacy and tolerability of larazotide acetate in protecting against gluten-induced intestinal permeability and gastrointestinal symptom severity in patients with celiac disease.

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Available from: Daniel A Leffler
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    • "Additionally, patients who were treated with larazotide acetate had significantly fewer GI symptoms compared with those taking a placebo. Larazotide acetate also blunted the increase in anti-tissue transglutaminase (tTG) antibodies in response to a prolonged challenge with gluten [Leffler et al. 2012, 2015; Kelly et al. 2013]. This paper examines the clinical trials and in vitro studies related to larazotide acetate in the treatment of CD. "
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    ABSTRACT: Celiac disease (CD) is a common chronic immune disease triggered by gluten. Gliadin peptides pass through the epithelial layers, either paracellularly or transcellularly, to launch a potent adaptive immune response in the lamina propria. This aberrant immune response leads to diverse gastrointestinal and extra-gastrointestinal symptoms. Currently, the only treatment for CD is a strict lifelong adherence to a gluten-free diet (GFD), which can be challenging. An early effect of gluten in CD is an increase in gut permeability. Larazotide acetate, also known as AT-1001, is a synthetic peptide developed as a permeability regulator primarily targeting CD. In vitro studies indicate that larazotide acetate is capable of inhibiting the actin rearrangement caused by gliadin and clinical studies have been conducted using this peptide as a therapy for CD.
    Full-text · Article · Jan 2016 · Therapeutic Advances in Gastroenterology
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    • "Conversely, the same test was not a reliable instrument to detect asymptomatic CD subjects in a mass screening project [29]. Furthermore, IPT did not perform optimally in two recent trials of larazotide acetate in measuring changes in intestinal permeability after a 14-day [30] or 6-week [31] gluten challenge. "
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    ABSTRACT: A gluten-free diet (GFD) is currently the only available treatment for patients with celiac disease (CD). Several clinical trials have demonstrated that most celiac patients can tolerate a medium-high quantity of oats without any negative clinical effects; however, the inclusion of oats in GFD is still a matter of debate. In this study, Italian children with CD were enrolled in a 15-month, randomized, double-blind, placebo-controlled multicenter trial. Participants were randomized in two groups following either A-B treatment (6 months of diet "A", 3 months of standard GFD, 6 months of diet "B"), or B-A treatment (6 months of diet "B", 3 months of standard GFD, 6 months of diet "A"). A and B diets included gluten-free (GF) products (flour, pasta, biscuits, cakes and crisp toasts) with either purified oats or placebo. Clinical data (Gastrointestinal Symptoms Rate Scale [GSRS] score) and intestinal permeability tests (IPT), were measured through the study period. Although the study is still blinded, no significant differences were found in GSRS score or the urinary lactulose/mannitol (L/M) ratio between the two groups after 6 months of treatment. These preliminary results suggest that the addition of non-contaminated oats from selected varieties in the treatment of children with CD does not determine changes in intestinal permeability and gastrointestinal symptoms.
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    ABSTRACT: One of the most important and overlooked functions of the gastrointestinal tract is to provide a dynamic barrier to tightly controlled antigen trafficking through both the transcellular and paracellular pathways. Intercellular tight junctions (TJ) are the key structures regulating paracellular trafficking of macromolecules. Although steady progress has been made in understanding TJ ultrastructure, relatively little is known about their pathophysiological regulation. Our discovery of zonulin, the only known physiological modulator of intercellular TJ described so far, increased understanding of the intricate mechanisms that regulate gut permeability and led us to appreciate that its up-regulation in genetically susceptible individuals may lead to immune-mediated diseases. This information has translational implications, because the zonulin pathway is currently exploited to develop both diagnostic and therapeutic applications pertinent to a variety of immune-mediated diseases.
    No preview · Article · Aug 2012 · Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association
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