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

Paterson, Blake M.; Lammers, Karen M.; Arrieta, Marie‐Claire; Fasano, Alessio; Meddings, Jon

doi:10.1111/j.1365-2036.2007.03413.x

Cited by 248 publications

(189 citation statements)

References 16 publications

(22 reference statements)

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“…Addition of zonulin may prevent T-c ell mediated stimulation in CD. In a double-blind randomized plac ebo-c ontrolled study of milligram doses of AT-1001, an inhibitor of parac ellular permeability derived from Vibrio cholera, prevented the expec ted inc reases in intestinal permeability in subjec ts with CD c hallenged with gluten [117] . AT-1001 use is also assoc iated with a diminution in the antic ipated rise of interferon-gamma levels.…”

Section: Alternatives To a Gluten Free Dietmentioning

confidence: 99%

Recent advances in celiac disease

Freeman

Chopra²,

Clandinin³

et al. 2011

WJG

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Celiac disease now affects about one person in a hundred in Europe and North America. In this review, we consider a number of important and exciting recent developments, such as clinical associations, HLA-DQ2 and HLA-DQ8 predispositions, the concept of potential celiac disease, the use of new imaging/endoscopy techniques, and the development of refractory disease. This review will be of use to all internists, pediatricians and gastroenterologists.

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Section: Alternatives To a Gluten Free Dietmentioning

confidence: 99%

Recent advances in celiac disease

Freeman

Chopra²,

Clandinin³

et al. 2011

WJG

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“…The key role of gliadin-induced zonulin release and subsequent loss of intestinal barrier function in CD pathogenesis has been supported by clinical trials with the zonulin inhibitor AT1001. 50 Gliadin interaction with macrophages initiates signaling through a TLR-like pathway, resulting in the establishment of a pro-inflammatory (Th1-type) cytokine milieu that results in mononuclear cell infiltration into the submucosa. This, in turn, may permit the interaction of T cells with antigen-presenting cells, including macrophages, leading ultimately to the antigen-specific adaptive immune response seen in patients with CD.…”

Section: Specific Autoimmune Diseases In Which Zonulin Involvement Hamentioning

confidence: 99%

Physiological, Pathological, and Therapeutic Implications of Zonulin-Mediated Intestinal Barrier Modulation

Fasano

2008

The American Journal of Pathology

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The anatomical and functional arrangement of the gastrointestinal tract suggests that this organ, beside its digestive and absorptive functions, regulates the trafficking of macromolecules between the environment and the host through a barrier mechanism. Under physiological circumstances, this trafficking is safeguarded by the competency of intercellular tight junctions, structures whose physiological modulation is mediated by, among others, the recently described protein zonulin. To prevent harm and minimize inflammation, the same paracellular pathway, in concert with the gut-associated lymphoid tissue and the neuroendocrine network, controls the equilibrium between tolerance and immunity to nonself antigens. The zonulin pathway has been exploited to deliver drugs, macromolecules, or vaccines that normally would not be absorbed through the gastrointestinal mucosal barrier. However, if the tightly regulated trafficking of macromolecules is jeopardized secondary to prolonged zonulin up-regulation, the excessive flow of nonself antigens in the intestinal submucosa can cause both intestinal and extraintestinal autoimmune disorders in genetically susceptible individuals. This new paradigm subverts traditional theories underlying the development of autoimmunity, which are based on molecular mimicry and/or the bystander effect, and suggests that the autoimmune process can be arrested if the interplay between genes and environmental triggers is prevented by reestablishing intestinal barrier competency. Understanding the role of zonulin-dependent intestinal barrier dysfunction in the pathogenesis of autoimmune diseases is an area of translational research that encompasses many fields. The intestinal epithelium is the largest mucosal surface, providing an interface between the external environment and the mammalian host. Its exquisite anatomical and functional arrangements and the finely-tuned coordination of digestive, absorptive, motility, neuroendocrine, and immunological functions are testimonial of the complexity of the gastrointestinal (GI) system. Also pivotal is the regulation of molecular trafficking between the intestinal lumen and the submucosa via the paracellular space. The dimensions of the paracellular space are estimated to be between 10 and 15 Å, suggesting that under physiological circumstances, solutes with a molecular radius exceeding 15 Å (ϳ3.5 kDa) will be excluded from this uptake route. Macromolecule trafficking is dictated mainly by intestinal paracellular permeability, the regulation of which depends on the modulation of intercellular tight junctions (TJs). A century ago, TJs were conceptualized as a secreted extracellular cement forming an absolute and unregulated barrier within the paracellular space. The contribution of the paracellular pathway of the GI tract to the general economy of molecule trafficking between environment and host, therefore, was judged to be negligible. It is now apparent that TJs are extremely dynamic structures involved in several key functions of the intestinal epithe...

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“…Another way of action is the preservation of the structure of intestinal barrier: the modulation of the intestinal permeability by zonulin antagonist AT-1001 is a completed phase IIb complementary approach with promising results [45]. Also the administration of a specific anti-IL-15 antibody was able to reverse the intestinal barrier damage through the induction of apoptosis of intraepithelial lymphocytes [46], however clinical studies for CD have been not yet performed.…”

Section: Therapymentioning

confidence: 99%

Coeliac Disease: From Triggering Factors to Treatment

Sziksz

Vörös

Veres

et al. 2016

IJCD

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Coeliac disease (CD) or gluten sensitive enteropathy is one of the most common inflammatory diseases of the small intestine with estimated prevalence of 1% in the population. Its incidence is increasing and seems to be higher than expected in the pediatric population associated with unfavorable impact on the quality of life. The aim of the present review is to highlight the main triggering factors leading to the development of CD and its pathomechanism with a special outlook to the recent therapeutic approaches.

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

Cited by 248 publications

References 16 publications

Recent advances in celiac disease

Recent advances in celiac disease

Physiological, Pathological, and Therapeutic Implications of Zonulin-Mediated Intestinal Barrier Modulation

Coeliac Disease: From Triggering Factors to Treatment

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