Article

The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: A proof of concept study

Alba Therapeutics Corporation, Baltimore, MD 21201, USA.
Alimentary Pharmacology & Therapeutics (Impact Factor: 5.48). 10/2007; 26(5):757-66. DOI: 10.1111/j.1365-2036.2007.03413.x
Source: PubMed

ABSTRACT Lifelong adherence to a strict gluten-free diet is the cornerstone of coeliac disease treatment. Elucidation of disease pathogenesis has created opportunities for novel therapeutic approaches to coeliac disease. AT-1001 is an inhibitor of paracellular permeability whose structure is derived from a protein secreted by Vibrio cholerae.
To determine the safety and tolerability of 12 mg doses of AT-1001 in coeliac disease subjects challenged with gluten.
An in-patient, double-blind, randomized placebo-controlled safety study utilizing intestinal permeability, measured via fractional excretions of lactulose and mannitol, as an exploratory measure of drug efficacy.
Compared to placebo, no increase in adverse events occurred in patients exposed to AT-1001. Following acute gluten exposure, a 70% increase in intestinal permeability was detected in the placebo group, while none was seen in the AT-1001 group. Interferon-gamma levels increased in four of seven patients (57%) of the placebo group, but only in four of 14 patients (29%) of the AT-1001 group. Gastrointestinal symptoms were more frequently detected in the placebo group when compared to the AT-1001 group (P = 0.018).
AT-1001 is well tolerated and appears to reduce intestinal barrier dysfunction, proinflammatory cytokine production, and gastrointestinal symptoms in coeliacs after gluten exposure.

Download full-text

Full-text

Available from: Alessio Fasano, Oct 06, 2014
0 Followers
 · 
98 Views
  • Source
    • "In a pilot study, AT-1001 was well tolerated with no increase in adverse events compared to placebo, the majority of adverse events being GI disorders, mostly frequenty diarrhoea [231]. A trend to reduce intestinal barrier permeability, IFN-production and GI symptoms after acute gluten exposure was observed although this must be confirmed. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The intestinal epithelial monolayer constitutes a physical and functional barrier between the organism and the external environment. It regulates nutrients absorption, water and ion fluxes, and represents the first defensive barrier against toxins and enteric pathogens. Epithelial cells are linked together at the apical junctional complex by tight junctions that reduce the extracellular space and the passage of charge entities while forming a physical barrier to lipophilic molecules. Cultured intestinal epithelial cells have been extensively used to study intestinal absorption of newly synthesized drugs and the regulation of tight junctions structure and function. In vitro mild irritants, proinflammatory cytokines, toxins and pathogens, and adverse environmental conditions open tight junctions and increase paracellular permeability, an effect often accompanied by immune activation of the enterocytes. Conversely, inhibition of proinflammatory cytokines, exposure to growth factors and probiotics, among others, exert a protective effect. Impaired barrier function results from activation of signalling pathways that lead to alteration of junctional proteins expression and/or distribution. In vivo, intestinal barrier dysfunction is associated with various intestinal and non-intestinal disorders including inflammatory bowel disease, celiac disease, and diarrhoeal infection. This review will describe the current knowledge of the mechanisms regulating tight junctions and intestinal permeability, how these findings have lead to a better understanding of barrier alteration in human intestinal disorders, and what the emerging therapies to treat these pathologies are.
    Current Medicinal Chemistry 01/2011; 18(3):398-426. DOI:10.2174/092986711794839179 · 3.85 Impact Factor
  • Source
    • "For this reason, CD patients often do not fully adhere to GFD and therefore remain exposed to a high morbidity risk. Consequently, new strategies are being actively pursued to find new treatments or to eliminate noxious prolamins from cereal grains [11] [12] [13] [14]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Natural or induced variations in the noxiousness of gluten proteins for celiac disease (CD) patients are currently being investigated for their potential in breeding wheat crops with reduced toxicity. We evaluated the bread wheat line C173 for its effects on the in vitro-grown duodenal mucosa of CD patients. In vitro-grown duodenal mucosa biopsies of 19 CD patients on a gluten-free diet were exposed to peptic/tryptic-digested prolamins from bread wheat line C173 lacking gliadin-glutenin subunits, analyzed for morphology, cytokine and anti-tTG antibody production, and compared with mucosa biopsies exposed to prolamins from wild-type cv. San Pastore. Duodenal mucosa biopsies exposed to prolamins from C173 and San Pastore released higher amounts of IFN-γ, IL-2, IL-10 and anti-tTG antibodies in the culture medium than untreated controls. The line C173 differed from cv. San Pastore as it did not produce negative effects on enterocyte height, suggesting that manipulating prolamin composition can affect innate immune responses of CD mucosa to wheat gluten. Our data demonstrated that this gliadin-deficient wheat has a lower direct toxicity but activates an immunologic reaction of the duodenal mucosa like that of the common wheat species.
    Digestive and Liver Disease 01/2011; 43(1):34-9. DOI:10.1016/j.dld.2010.05.005 · 2.89 Impact Factor
  • Source
    • "When the integrity of the tj system is compromised as in CD, a paracellular leak and an inappropriate immune response to environmental antigens develops [74]. The possibility to use the synthetic peptide inhibitor of zonulin receptor AT-1001 to recover intestinal permeability was explored in a Phase I clinical trial [75]. The objective of this study was to establish the safety and tolerability of oral AT-1001 in CD patients in remission challenged with a single dose of gluten. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The gut-associated lymphoid tissue is deputed both to protect from infectious diseases and to evoke immune tolerance. Efficient responses need mucosal adjuvants: starting from cholera toxin, new variants of cholera toxin were developed depleted of toxicity. In addition, lipid colloidal particles, bacterial DNA, and probiotics have been experimented. Tolerance is currently induced by means of the B subunit of cholera toxin, whereas new strategies encompass the use of probiotics, expansion of regulatory T cells and blocking of paracellular entry of antigens. Finally, we report different approaches developed for celiac disease, an immune-mediated disease whose triggering antigen is known.
    International Reviews Of Immunology 12/2009; 28(6):446-64. DOI:10.3109/08830180903236486 · 5.28 Impact Factor
Show more