THURSDAY, July 24 (HealthDay News) — Researchers believe they have finally answered a basic question about the cause of celiac disease — where in the body does the wheat protein gluten enter one’s system?
A study published in the July issue of Gastroenterology identifies the CXCR3 receptor in the intestine as a gluten gateway. When people with celiac disease eat gluten, the protein triggers their immune system to attack the body, causing a wide range of serious health problems.
“This is a scientific question that had never been answered before,” Dr. Alessio Fasano, medical director of the Center for Celiac Research at the University of Maryland School of Medicine, said in an university news release. “It is not only significant in the basic science of autoimmune disorders such as celiac disease, but in therapeutic approaches for the future. This opens a new scientific paradigm for the study of immunity.”
The research team found that gliadin, the part of gluten that causes the most trouble for those with celiac disease, binds to the CXCR3 receptor. This results in the release of zonulin, a human protein that lowers the intestinal barrier to make it more permeable. While this effect is temporary in most people, the barrier stays down for long periods of time in people with celiac disease, causing disruption in the body’s system.
The finding may help in research on the cause and treatment for other autoimmune diseases, Fasano said. People with type 1 diabetes and multiple sclerosis may experience a similar condition in which offending antigens enter the body through this gateway in the intestines.
“For the first time, we have evidence of how the foreign antigen gains access to the body, causing the autoimmune response,” said Fasano, who is also a pediatric gastroenterologist at the University of Maryland Medical Center. “Further study is needed, but this could allow us to intervene before the zonulin is either released or activated, preventing the immune response altogether.”
Milestone Marks the First Time a European Patient with Active Celiac Disease has Enrolled in a Clinical Trial for an Investigational Medication from Alba Therapeutics
Last update: 8:22 p.m. EST Nov. 11, 2008
BALTIMORE, Nov 11, 2008 /PRNewswire via COMTEX/ –
Alba Therapeutics Corporation announced today that for the first time, a European patient with active celiac disease has been enrolled in its clinical trial to investigate a treatment for the disease. Alba has enrolled and randomized the newly diagnosed patient from Spain in an eight-week Phase IIb trial with oral larazotide acetate, a tight junction regulator, for the treatment of patients with active celiac disease (CD). The global multi-center, randomized, double-blind, placebo-controlled study will evaluate the clinical and histological efficacy, safety and tolerability of larazotide acetate in 106 active CD subjects adhering to a gluten-free diet, while assessing improvement in the clinical signs and symptoms of celiac disease.
“These are decisive times for our desire to one day be able to offer our celiac patients a treatment that allows them to live more normal lives,” said Dr. Gemma Castillejo, MD, a pediatric gastroenterologist and principal investigator in the study. Dr. Castillejo, a leading European celiac expert from the Sant Joan de Reus University Hospital in Reus, Spain added, “I believe this clinical trial has the potential to be a turning point in the search for treatments for celiac disease.”
“This is a major milestone for the celiac community in Europe,” stated Francisco Leon, MD, PhD, Vice President, Clinical Development and Medical Affairs of Alba. “This is Alba’s sixth human trial with larazotide acetate, and we are excited to be advancing our investigational program for larazotide acetate in this important region of the world.”
About Celiac Disease
Celiac disease is an inherited autoimmune disorder where gluten has been identified as the environmental trigger of the disease. Gluten is an ingested protein found in wheat, barley and rye. Gluten is broken down into gliadin which can pass through the intestinal epithelial barrier during times of increased intestinal permeability. The ingestion of gluten causes an immune response which triggers an inflammatory reaction in the small intestine. This then causes damage to the villi in the small intestine and can lead to total villous atrophy in celiac disease. This results in varying symptoms such as fatigue, skin rash, anemia, fertility issues, joint pain, weight loss, pale sores inside the mouth, tooth discoloration or loss of enamel, depression, chronic diarrhea or constipation, gas and abdominal pain. The immunology and nutritional abnormalities in celiac disease can potentially result in long- term complications such as osteoporosis, refractory sprue, small intestinal cancer, and lymphoma.
Celiac disease is a growing public health concern, affecting approximately 3 million people in the United States and over 6.5 million people worldwide. The only current management of celiac disease is complete elimination of gluten from the diet, which can be very difficult to implement in practice. Additionally, the response to the gluten-free diet is poor in up to 30% of patients, and dietary nonadherence is the chief cause of persistent or recurrent symptoms.(1)
(1) Green, P, and Cellier, C, Review Article,
Medical Progress, Celiac Disease, N ENGL J MED
About “Larazotide Acetate”
Larazotide acetate is an experimental medicine and a tight junction regulator that acts locally by inhibiting the opening of tight junctions in epithelial cells lining the small intestine. In celiac disease, gluten crosses the epithelial barrier and stimulates the immune system, leading to cytokine release, gut inflammation, and opening of tight junctions. This leads to increased paracellular permeability, increased entry of gluten and the establishment of an intestinal permeability-inflammation loop. Larazotide acetate inhibits tight junction opening triggered by both gluten and inflammatory cytokines, thus reducing uptake of gluten. Larazotide acetate disrupts the intestinal permeability-inflammation loop, and reduces symptoms associated with celiac disease. Larazotide acetate is orally formulated, has been granted “Fast Track” designation by the U.S. Food and Drug Administration for the treatment of celiac disease, and is also being evaluated for the treatment of Crohn’s Disease.
For more information about Alba’s clinical trials, please visit the www.clinicaltrials.gov web site and search for Alba Therapeutics.
Alba Therapeutics Corporation is a privately held, clinical-stage biopharmaceutical company focused on the discovery, development, and commercialization of therapies to treat autoimmune and inflammatory diseases and is located in Baltimore, Maryland. Alba’s technology platform is based upon a key pathway that regulates the assembly and disassembly of tight junctions in cell barriers throughout the body. As a result of its unique technology platform, Alba is a leader in mucosal biology and has developed a pipeline of innovative therapeutic candidates that has the potential to modify the course of disease and significantly improve upon existing treatments for a wide range of diseases such as celiac disease, Crohn’s disease, and Asthma/COPD or acute lung injury.
Scientists who last year identified a new genetic risk factor for coeliac disease, have, following continued research, discovered an additional seven gene regions implicated in causing the condition. The team, lead by David van Heel, Professor of Gastrointestinal Genetics at Barts and The London School of Medicine and Dentistry, have further demonstrated that of the nine coeliac gene regions now know, four of these are also predisposing factors for type 1 diabetes. Their research sheds light not only on the nature of coeliac disease, but on the common origins of both diseases. It is published online today (2 March 2008) in Nature Genetics.
Professor van Heel and his team, including collaborators from Ireland, the Netherlands, and the Wellcome Trust Sanger Institute, first performed a genome wide association study in coeliac disease. Genetic markers across the genome were compared in coeliac disease subjects versus healthy controls. They then assessed around 1,000 of the strongest markers in a further ~ 5,000 samples. Their results identified seven new risk regions, six of which harbour important genes critical in the control of immune responses, highlighting their significance in the development of the disease.
Coeliac disease is common in the West, afflicting around 1 per cent of the population. It is an immune-mediated disease, triggered by intolerance to gluten (a protein found in wheat, barley and rye containing foods), that prevents normal digestion and absorption of nutrients. If undetected it can lead to a number of often severe problems among them anaemia, poor bone health, fatigue and weight loss. Currently only a restricted diet can diminish symptoms.
Professor van Heel said: “So far our findings explain nearly half of the heritability of coeliac disease – now studies with many more samples from individuals with coeliac disease are needed to identify the precise causal genetic variants from each region, and understand how these influence biological processes.”
The research was funded by Coeliac UK and The Wellcome Trust. Coeliac disease case studies are available for interview from Coeliac UK upon request.
The paper, ‘Newly identified genetic risk variant for celiac disease related to the immune response’ is published online, on 2 March 2008, in Nature Genetics.
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Notes to editors:
Barts and The London School of Medicine and Dentistry offers international levels of excellence in research and teaching while serving a population of unrivalled diversity amongst which cases of diabetes, hypertension, heart disease, TB, oral disease and cancers are prevalent, within east London and the wider Thames Gateway. Through partnership with our linked trusts, notably Barts and The London NHS Trust, and our associated University Hospital trusts – Homerton, Newham, Whipps Cross and Queen’s – the School’s research and teaching is informed by an exceptionally wide ranging and stimulating clinical environment.
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