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    AT-1001 Shows Promise for those with Celiac Disease, But Likely not a Silver Bullet


    Jefferson Adams

    Celiac.com 05/27/2008 - People with celiac disease know all too well that the only effective treatment at present is faithfully following a gluten-free diet. There’s been a lot of talk about various therapies and enzyme treatments that would allow people with celiac disease to return to a normal diet. Talk to anyone who suffers from celiac disease and they’ll likely have a personal horror story about a time when they had an unhappy episode of cross-contamination.

    So, the idea of a drug that would prevent such symptoms is appealing, and the goal, desirable. The chief cause of recurring symptoms in celiac disease is accidental gluten exposure, usually through cross-contamination. Cross-contamination doesn’t always mean food. Gluten is a common ingredient in many medicines and vitamins, and exposure in celiacs can cause diarrhea, weight loss, abdominal pain, anemia and oral ulcerations in the short-term, and myriad other problems in the long-run.

    The drug AT-1001 is a good example of how the realities are playing out on the front-lines of science. AT-1001 is an enzyme therapy that has promised some degree of protection from gluten exposure in people with celiac disease.

    A team of researches recently set out to assess the effectiveness of AT-1001 in preventing gluten from crossing the gut barrier by reversing the defective barrier mechanism. This required evaluating intestinal permeability between those exposed to gluten after taking AT-1001, those exposed without AT-1001, and control groups. The of intestinal function is done by gauging the absorption rates of various sugars.

    Early testing of AT-1001 showed some progress and a significant rate of protection of celiac patients exposed to wheat proteins. The research team looked at 86 subjects with celiac disease. The patients were divided into three groups. The first group was given placebo AT-1011 and challenged with gluten, the second group was given either active or placebo AT-1001, while the third group was given gluten and active AT-1001.

    After the first week, all subjects showed improvement, possibly due to closer adherence to a gluten-free diet. At three weeks, those given AT-1001 showed substantial improvement over the group given gluten and placebo AT-1001, including reduced intestinal permeability and fewer symptoms of gluten toxicity.

    The problem is that while AT-1001 shows a degree of promise, the results are so far underwhelming. The research team noted that the degree of improvement did not match the primary study. The results are, however, strong enough to encourage researchers to conduct a larger trial of AT-1001, which is currently underway.

    It’s important to remember that celiac disease is an immune disorder and no immune disorder has ever been fully cured. So, the idea of people with celiac disease being able to take a pill and head out for a night of pizza and beer without the standard celiac-related reactions is far-fetched at best. At best, such drugs would likely help to prevent cross-contamination, rather than conveying immunity to gluten proteins.

    Until then, stay tuned…best of luck with the gluten-free diet!

    Presented by Dr. Leffler at the 2009 Digestive Disease Week on Tuesday, May 20 at 10:45 a.m. Pacific Time in room 10, San Diego Convention Center.

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    Guest Aunt Babe

    Posted

    Well, if my celiac aunt can go out and have grilled chicken, a salad with Gluten Free dressing, and a baked potato without getting sick by taking this drug then it's a winner in my book!!

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    Guest Bonnie M

    Posted

    I have been recently diagnosed with celiac disease. I don't have trouble as long as I'm eating what I fix, it's getting it by accident somewhere that scares me. I hope they perfect this soon!

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    Guest lildrmr2

    Posted

    I have had the celiac diagnosis for over 1 year now. If we go out I get sick. I'm only safe if we stay home. I look forward to this medication. Then I could pretend to eat normal.

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  • About Me

    Jefferson Adams earned his B.A. and M.F.A. at Arizona State University, and has authored more than 2,000 articles on celiac disease. His coursework includes studies in biology, anatomy, medicine, and science. He previously served as Health News Examiner for Examiner.com, and provided health and medical content for Sharecare.com.

    Jefferson has spoken about celiac disease to the media, including an appearance on the KQED radio show Forum, and is the editor of the book Dangerous Grains by James Braly, MD and Ron Hoggan, MA.

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    Scott Adams
    Journal of Clinical Gastroenterology 2003; 36(3):219-221
    Celiac.com 03/28/2003 - A study by Antonio Tursi, M.D, et al, was recently conducted to evaluate the correlation between the degree of histologic intestinal damage in celiac patients and their level of positivity (serum value) to anti-tissue transglutaminase antibodies (anti-tTG). The study looked at 119 adult celiac patients who were diagnosed consecutively (47 men and 72 women; mean age, 28 years; range, 22-51 years), and were stratified for histologic damage according to Marsh classification. The final step was to compare their Marsh histologic intestinal damage classification with their anti-tTG serum values. Here are their results:


    Marsh I lesions were present in 13 patients (10.92%), Marsh II in 24 anti-tTG (20.16%), Marsh IIIa in 27 anti-tTG (22.68%), Marsh IIIb in 31 anti-tTG (26.05%) and Marsh IIIc in 24 anti-tTG (20.16%). Anti-tTG positivity was ranging from 1 of 13 anti-tTG (7.69%) in Marsh I lesions to 23 of 24 anti-tTG (95.83%) in Marsh IIIc lesions respectively (P
    The researchers conclude that the mean serum value in celiacs with severe enteropathy (Marsh IIIb-c lesions) was higher than in those with only slight enteropathy (Marsh I-IIIa). Further, serologic test results in the absence of histologic evaluation (biopsy) may "underestimate the real prevalence of celiac disease," thus delaying a proper diagnosis and putting patients at risk for a large variety of serious health problems.

    Scott Adams
    Celiac.com 02/09/2006 - Do not try this at home. If you have celiac disease you need to remain on a gluten-free diet. This particular study, as indicated below, involved only one person--which is far too small of a sample to draw any solid conclusions from. It does, however, offer some hope that there may be other unknown factors that cause this disease--perhaps factors that can be reversed or kept in check. Many more studies will be needed to determine this. After reading and publishing much of Roy Jamrons work, we thought his comments on this study were very interesting and have reproduced them here.
    Comments by Roy Jamron:
    This is interesting, a case of reintroducing gluten to a celiac woman after a 10 year gluten-free diet with no symptoms of celiac disease showing up during a 15 month follow up study. It would be interesting if she remains symptom free in subsequent years.
    It does bring up the idea of a gluten-ingesting bacteria link which I proposed in my article, Are Commensal Bacteria with a Taste for Gluten the Missing Link in the Pathogenesis of Celiac Disease?. In that article I proposed that a bacteria capable of transporting and internalizing gluten peptides resistant to breakdown could initiate a T cell immune response to gluten. Antigen presenting cells (dendritic cells) might present gluten peptides internalized by the bacteria along with peptides and chemical signals from the bacteria to T cells. The T cells would not be able to distinguish the gluten peptides from the bacteria peptides and would, therefore, initiate an immune response to gluten peptides as though they were components from pathogenic bacteria. The presence or non-presence of such a bacteria in twins offered an explanation as to why one identical twin could develop celiac disease and not the other.
    After 10 years on a gluten-free diet, it is possible that the numbers of such gluten-ingesting bacteria might diminish to a level too few to initiate a gluten immune response, especially if the bacteria largely depend on gluten for nutrition. So, like the twin who does not develop celiac disease, she remains symptom free.
    I urged researchers to look for such gluten-ingesting bacteria in my article, and I continue to urge such research. Such bacteria could be found through the use of immunogold electron microscopy. This technique permits gluten peptides to be bound to and labeled with gold particles which show up as distinct opaque spots under the electron microscope. Such spots found within microscopic cross sections of fecal bacteria samples would identify gluten-ingesting bacteria.
    Abstract of Study:


    An Attempt of Specific Desensitizing Treatment with Gliadin in Celiac Disease
    Int J Immunopathol Pharmacol. 2005 Oct-Dec;18(4):709-14.
    Gluten-free diet is the current treatment of celiac disease. We decided to verify the occurrence of histological and serological modification and/or clinical manifestations during a gradual and progressive introduction of gliadin in the diet and if it may induce a tolerance to food, as it occurs in allergic patients. We studied the case of a celiac woman with complete clinical and histological remittance after 10 years of gluten free diet. She took increasing daily doses of gliadin, reaching the final dose of 9 g of gliadin (15 g of gluten) in 6 months. Then she started a free dietary regimen. During the 15-month follow-up period esophago-gastro-duodenoscopy showed normal Kerckring folds and villi. Anti-gliadin, anti-endomysium and anti-tissue-transglutaminase antibodies, as well as the haematological and biochemical parameters remained normal. Our results represent a new approach in research concerning celiac disease, and could provide a future line of study for its management.

    Jefferson Adams
    Celiac.com 11/29/2007 - Studies have documented the role of gut microbiotic bacteria in diseases involving chronic inflammation, such as celiac disease, yet there is scant data on such bacteria that is specific to people with celiac disease. A team of Spanish and Italian researchers from three different hospitals and universities made up of Yolanda Sanz, Ester Sanchez, Marta Marzotto, Miguel Calabuig, Sandra Torriani, and Franco Dellaglio set out to determine what differences might exist between the microbiotic bacteria in the guts of children with celiac disease compared to a healthy control group of their peers.
    The team conducted a denaturing gradient gel electrophoresis analysis of fecal samples from both the celiac and the control groups. They found that children with celiac disease had a more diverse profile of intestinal microbiotic bacteria than did the healthy control subjects.
    The children with celiac disease were characterized by the presence of Lactobacillus curvatus, Leuconostoc mesenteriodes, and Leuconostoc carnosum, whereas the members of the healthy control group were characterized by the presence of Lactobacillus casei. Conversely, the bifidobacterium population was much greater in the members of the healthy control group than among the children with celiac disease.
    The healthy control group showed particularly high populations of bifidobacterium adolescentis compared to the celiac patients. The team has called for more research into which populations of the various gut microbial are affected by celiac disease. This may lead to a possible role for probiotics and/or prebiotics in returning the balance of the gut microbes in those with celiac disease.
    FEMS Immunol Med Microbiol. 2007 Dec;51(3):562-8


    Jefferson Adams
    Celiac.com 09/17/2009 - Just after the turn of this century, researchers at the University of Maryland School of Medicine discovered that a mysterious human protein called zonulin played a key role in celiac disease and other autoimmune disorders, such as multiple sclerosis and diabetes.
    The situation might be likened to sailors who've an island, but not explored it. Researchers knew Zonulin existed, and some of its influences, but little else about it. Recently, a team of scientists led by Alessio Fasano, M.D., set out to isolate and decode zonulin. Their results are in, and Fasano's research team has successfully identified zonulin as a molecule called haptoglobin 2 precursor.
    Understanding the exact biochemistry of zonulin, the exact make-up of the protein molecule, is crucial to a comprehensive study of zonulin and its relationship to numerous inflammatory disorders.
    Dr. Fasano is a professor of pediatrics, medicine and physiology and director of the Mucosal Biology Research Center and the Center for Celiac Research at the University of Maryland School of Medicine.
    Haptoglobin is a molecule that has been known to scientists for many years. It was identified as a marker of inflammation in the body. Haptoglobin 1 is the original form of the haptoglobin molecule, and scientists believe it evolved 800 million years ago. Haptoglobin 2 is a version found only in humans. Scientists believe the mutation occurred in India about 2 million years ago, spreading gradually among increasing numbers of people throughout the world.
    Dr. Fasano's study showed that zonulin is the precursor molecule for haptoglobin 2 — that is, it is an immature molecule that develops into haptoglobin 2. Scientists previously believed that such precursor molecules played no role in the body other than to develop into the molecules they were destined to become.
    But Dr. Fasano's study reveals precursor haptoglobin 2 as the first precursor molecule to serve another function altogether; that of opening a gateway in the gut, permitting gluten to pass through. People with celiac disease suffer from a sensitivity to gluten.
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    According to Dr. Fasano, the haptoglobin 2 molecule "could be a critical missing piece of the puzzle to lead to a treatment for celiac disease, other autoimmune disorders and allergies and even cancer, all of which are related to an exaggerated production of zonulin/pre-haptoglobin 2 and to the loss of the protective barrier of cells lining the gut and other areas of the body, like the blood brain barrier."
    "The only current treatment for celiac disease is cutting gluten from the diet, but we have confidence Dr. Fasano's work will someday bring further relief to these patients. Zonulin, with its functions in health and disease as outlined in Dr. Fasano's paper, could be the molecule of the century," says E. Albert Reece, M.D., Ph.D., M.B.A., dean of the School of Medicine, vice president for medical affairs of the University of Maryland and John Z. and Akiko K. Bowers Distinguished Professor.
    Dr. Fasano published his findings in the online version of the Proceedings of the National Academy of Sciences, appearing the week of September 7, 2009.


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