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    Jefferson Adams

    Can Gliadin Nanoparticles Cure Celiac Disease in Humans?

    Reviewed and edited by a celiac disease expert.

    Gliadin nanoparticles trigger immune tolerance to gliadin in mouse models of celiac disease. Could celiac disease be treated, and potentially cured, by restoring T-cell tolerance to gliadin in humans?

    Can Gliadin Nanoparticles Cure Celiac Disease in Humans? - Platinum_nanoparticles. Image: CC BY-SA 4.0--PieroSpeleo
    Caption: Platinum_nanoparticles. Image: CC BY-SA 4.0--PieroSpeleo

    Celiac.com 03/28/2020 - In theory, celiac disease could be treated, and potentially cured, by restoring T-cell tolerance to gliadin. A team of researchers recently set out to investigate the safety and efficacy of negatively charged, 500 nm, poly (lactide-co-glycolide) nanoparticles encapsulating gliadin protein (TIMP-GLIA) in 3 mouse models of celiac disease. 

    The research team included Tobias L. Freitag, Joseph R. Podojil, Ryan M. Pearson, Frank J. Fokta, Cecilia Sahl, Marcel Messing, Leif C. Andersson, Katarzyna Leskinen, Päivi Saavalainen, Lisa I. Hoover, Kelly Huang, Deborah Phippard, Sanaz Maleki, Nicholas J.C. King, Lonnie D. Shea, Stephen D. Miller, Seppo K. Meri, and Daniel R. Getts.

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    Negatively charged, 500 nm, poly(lactide-co-glycolide) nanoparticles encapsulating gliadin protein (TIMP-GLIA) by antigen-presenting cells was shown to induce immune tolerance in other animal models of autoimmune disease. TIMP-GLIA did not elevate maturation markers on cultured human dendritic cells, or activate T cells from patients with active or treated celiac disease. 

    The team assessed the model 1 delayed-type hypersensitivity, the model 2 HLA-DQ8 transgenic, and the model 3 gliadin memory T cell enteropathy models of celiac disease.

    Injections of TIMP-GLIA substantially reduced gliadin-specific T cell generation in models 1 and 2. Further, injections reduced inflammatory cytokine secretion in all three models, circulating gliadin-specific IgG/IgG2c in models 1 and 2, ear swelling in model 1, gluten-dependent enteropathy in model 3, and body weight loss in model 3. 

    In model 1, the effects were shown to be dose dependent. Splenocytes from HLA-DQ8 transgenic mice given TIMP-GLIA nanoparticles, but not control nanoparticles, showed increased levels of FOXP3, and gene expression markers associated with improved tolerance.

    Injecting gluten-sensitive mice with TIMP-GLIA nanoparticles nearly eliminated the immune response to gliadin, and reduced markers of inflammation and enteropathy. This approach might be refined and used to develop new treatments for celiac disease in humans.

    Read more in Gastroenterology


    The researchers are variously affiliated with the Department of Bacteriology and Immunology; the Translational Immunology Research Program; the Department of Microbiology and Immunology at Cour Pharmaceutical Development Company, Northbrook, IL, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Helsinki, Finland; Precision for Medicine, Frederick, MD, USA; the Discipline of Pathology, School of Medical Sciences, Bosch Institute, Sydney Medical School, The University of Sydney, Sydney, Australia; the Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; and the Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

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    It is interesting to me , the comment of ear swelling reduced.  Both my daughter and granddaughter are diagnosed by genetics.  Both have a history of ear infections that have resulted in perforated ear drums.  Both have hearing aids because of hearing loss.  One of the perforations in my daughter healed when she was put on the gluten free diet but the hearing loss did not.

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  • About Me

    Jefferson Adams

    Jefferson Adams is Celiac.com's senior writer and Digital Content Director. He earned his B.A. and M.F.A. at Arizona State University, and has authored more than 2,500 articles on celiac disease. His coursework includes studies in science, scientific methodology, biology, anatomy, medicine, logic, and advanced research. He previously served as SF Health News Examiner for Examiner.com, and devised 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 "Cereal Killers" by Scott Adams and Ron Hoggan, Ed.D.

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  • Related Articles

    Jefferson Adams
    Celiac.com 02/05/2018 - TIMP-GLIA, a new nanoparticle-based celiac disease treatment currently under development by Cour Pharmaceuticals, has received Fast Track Designation from the US Food and Drug Administration (FDA). Phase 1 studies to assess the safety and tolerability of TIMP-GLIA are currently underway in the United States.
    TIMP-GLIA works in part by encapsulating a component of wheat within a nanoparticle. The treatment has resulted in gluten tolerance in numerous animal models. By encasing components of gluten proteins in a nanoparticle, Cour is hoping that the gluten will remain unrecognized by the body's immune system, at least until immune tolerance can be generated through non-inflammatory antigen presentation.
    The FDA created the fast track process to speed development, review and commercialization of drugs that target serious conditions and fill an unmet medical need. Fast Track Designation puts Cour in a "prime position to advance an innovative new approach for the treatment of Celiac Disease," said John J. Puisis, CEO of Cour Pharmaceuticals.
    Cour is investigating TIMP-GLIA as part of an effort to reprogram the body's immune system so patients develop a tolerance to gluten as a non-threatening substance and ultimately to reduce or reverse celiac disease without the need for immune suppressing drugs. Cour's approach is designed to work by encasing a component of wheat in a nanoparticle, and introducing that particle into a celiac disease patient. If it works as designed, the gluten will remain unrecognized by the body's immune system until tolerance can be achieved through non-inflammatory antigen presentation.
    The phase 1 clinical trial for TIMP-GLIA study is being conducted at centers in the United States. The objective of the study is to assess the safety and tolerability of TIMP-GLIA when administered intravenously (IV) as a single dose at ascending dose levels and as a repeat dose in subjects with celiac disease.
    All in all, this is another of many bold and encouraging efforts to treat or cure celiac disease that have arisen in the last few years. Look for news of success or failure over then next few years.
    Source: Pharmabiz.com

    Betty Wedman-St Louis, PhD, RD
    An experimental "vaccine" called Nexvax 2 is being scheduled for human clinical trials to evaluate its effectiveness in celiac disease. Immusan T is a biotechnology company focusing on developing therapeutic vaccines and received $40 million in 2017 to fund Nexvax 2 to reduce the "suffering of those with celiac disease since it is a serious inflammatory autoimmune disease caused from gluten".
    Since there is no cure for celiac disease except following a strict gluten-free diet, symptoms can vary greatly based on age and diet content. Children with DQ2 and DQ8 genes may have a swollen belly, chronic diarrhea and poor appetite which can cause delayed growth. Adults often experience abdominal pain, fatigue, anemia and joint pain. 
    When grain products- containing gluten and gliadin- are consumed tissue transglutaminase in the small intestinal lining signals an immune response that produces antibodies which attack the lining of the small intestine. This leads to malabsorption of nutrients from food. Nutrient deficiencies cause liver, bone and neuron damage resulting in abnormal growth, poor tissue repair and numerous symptoms.
    Allergy vs Auto-Immune Disease
    It is important to understand that celiac disease and dermatitis herpetiformis (itchy, blistery skin rash) are auto-immune disorders NOT an allergy to gluten. Allergies occur when the immune system overreacts to a compound causing the release of histamines. An auto-immune disorder results when the body misidentifies a substance as dangerous and causes the immune system to attack the body's own tissue.
    Celiac Disease Epidemic
    Celiac disease and gluten enteropathies are a growing epidemic in the U.S. and across the world due to the increasing use of processed foods and food additives that use grain products for thickening, stability and dietary supplement fillers. Environmental factors may contribute to a person becoming gluten intolerant even after decades of consuming gluten without suffering serious health consequences.
    How "Vaccine" Works
    The "vaccine" Nexvax 2 is designed to work similar to allergy shots according to Live Science (Nov. 9, 2018). The treatment involves twice weekly injections administered over a 16 week (4 months) period to reprogram T cells to begin to tolerate gluten and suppress immune destruction of the villi in the small intestine. No available data is currently available on the ingredients used in Nexvax 2 so safety can not be assessed at this point.
    What is known is that vaccines DO NOT mean immunization whether through injection or oral dosing. Immunization is a process for developing tolerance and protection against infections. Dorland's Medical Dictionary states vaccination means to "inject a suspension of attenuated or killed microorganisms administered for prevention or treatment of infectious disease".
    The Center for Disease and Prevention Control (CDC) states that vaccination does NOT guarantee immunity. Natural immunity comes only after a person recovers from the actual disease, and not all who receive a vaccination will have immunity. No vaccine is 100% effective because everyone's immune system reacts differently.
    Before lining up to participate in the clinical trials, adapt a more educated approach to vaccination safety regarding a disease managed very effectively by a healthy gluten-free, lectin-free diet. It is a personal decision for adults with celiac disease whether or not they chose to vaccinate. 
    It will be many years before the safety of this celiac disease "vaccine" can be established.  On a personal note: I have been a celiac for more than 70 years and would never consider a "vaccine" just so I didn't have to worry about hidden gluten. 

    Jefferson Adams
    Celiac.com 10/23/2019 - One approach to celiac disease that's been getting attention lately is the effort to develop ways to prevent the adverse immune reaction that is triggered by gluten that leads to gut damage in untreated celiacs. Several companies have tried that approach, including the promising, but now failed drug NexVax2. The idea is to train the immune system to become tolerant of gluten, kind of like the way allergists train the immune system to tolerate pollen, and thus, reduce or even eliminate allergic reactions.
    Data from a recent trial of new medical technology provides encouraging evidence that it is possible for people with celiac disease to achieve an immune tolerance to gluten, effectively reversing the autoimmune disease.
    The technology is a biodegradable nanoparticle containing gluten that teaches the immune system the antigen (allergen) is safe. The nanoparticle, called COUR nanoparticle, CNP-101, conceals the allergen in an innocuous cell covering, and convinces the immune system not to attack it.
    Celiac patients treated with CNP-101 were able to eat gluten with a substantial reduction in inflammation. The phase 2 results indicate that the treatment protects patients’ small intestine from gluten exposure, and point the way toward treatments that could allow celiac patients safely consume gluten in their diet.
    In addition to potentially reversing celiac disease, the technology, which uses a nanoparticle containing the antigen triggering the allergy or autoimmune disease, has the potential to treat myriad diseases and allergies, including multiple sclerosis, type 1 diabetes, peanut allergy, asthma, among others.
    The research team will present their findings on Oct. 22nd at the European Gastroenterology Week conference in Barcelona, Spain.
    The technology was devised in the lab of Stephen Miller, the Judy Gugenheim Research Professor of Microbiology and Immunology at Northwestern University Feinberg School of Medicine, who has refined it over decades.
    In addition to providing the first proof that the technology works in patients, the study shows that "we can encapsulate myelin into the nanoparticle to induce tolerance to that substance in multiple sclerosis models, or put a protein from pancreatic beta cells to induce tolerance to insulin in type 1 diabetes models,” said Miller. 
    The technology works by causing the immune system to see the allergen-loaded nanoparticle as innocuous debris, and to disregard it. Once ignored, the nanoparticle and its hidden antigen get eaten by a macrophage, kind of a garbageman that rids the body of cellular debris and pathogens.
    “The vacuum-cleaner cell presents the allergen or antigen to the immune system in a way that says, ‘No worries, this belongs here,'” Miller said. “The immune system then shuts down its attack on the allergen, and the immune system is reset to normal.”
    In the celiac trial, Miller's team loaded the nanoparticle with gliadin, the protein in gluten that triggers the adverse reaction in people with celiac disease.
    After a week of treatment, the patients consumed gluten for two weeks. Untreated celiac patients who ate gluten showed clear immune responses to gliadin and related damage to the small intestine. Meanwhile, celiac patients treated with CNP-101 showed 90% less immune-related inflammation than untreated patients. By preventing the inflammatory response, CNP-101 showed the ability to protect the gut from gluten-related damage.
    Most autoimmune diseases are currently treated with immune suppressants, which lessen symptoms, but degrade the immune response and carry the potential for toxic side-effects. CNP-101 does not work by suppressing the immune system, but by preventing the inflammatory response, and thus reversing the course of the autoimmune disease.
    Celiac disease a perfect target for the nanoparticle induced immune tolerance approach, because the triggers are well documented, and the disease has no other treatment than a gluten-free diet.
    CNP-101 has been granted Fast Track status by the U.S. Food and Drug Administration, and brought to patients in collaboration with Takeda Pharmaceuticals, which has acquired an exclusive global license to develop and commercialize this treatment for celiac disease.
    In addition to celiac disease, COUR is looking to develop treatments for peanut allergy and multiple sclerosis, and to expand their offerings to other autoimmune conditions, said John J. Puisis, president and chief executive officer of COUR.
    Read more in ScienMag.com

    Dr. Albert Zickmann
    Celiac.com 03/06/2020 - Celiac disease has an incidence of about 1% in the general population. It is an automimmune disease triggered by a proline-rich protein, gliadin, when it enters the small intestine and leaks into the wall of the small intestine (therefore the name leaky gut). Humans cannot break down proline-rich proteins. In healthy persons, gliadin passes through the gastrointestinal tract and is excreted in stool and urine without consequences. Celiac patients, build antibodies in the small intestine and these antibodies travel through the blood stream in all areas of the body. In some patients, there are no apparent symptoms or they can be very mild, while in others the symptoms are quite severe and are even associated with an increased risk of a certain type of intestinal cancer. 
    Researchers have identified that the body breaks down some of the components of gliadin, but the human body cannot break down and digest the components that contain the amino acid proline. There are two such segments of the gliadin molecule that are causing an inflammatory reaction and they are called 33-mer and 26-mer peptides, because they contain a 33 and respectively a 26 amino acid sequence.
    In an effort to prevent the gliadin molecule from leaking into the wall of the small intestine, a variety of methods have been tried. These include, closing the junctions through which gliadin leaks, encapsulating the gliadin molecule, and enzymatic degradation of the inflammatory segments of the gliadin molecule.  
    The smallest protein chain that can cause an inflammatory reaction is 9 amino acids long, and the goal would be to break down the gliadin molecule in segments of 8 or less amino acids. This has to happen before the gliadin molecule enters the small intestine and leak into the wall of the intestine. 
    The most commonly sold over-the counter enzymes are in the DPP-IV group, and while they are in fact very effective in breaking down gliadin's smaller segments, they cannot break down the proline rich areas in segments of less than 9 amino acids, and are therefore not effective in preventing an inflammatory reaction. 
    The three enzymes that have shown promising results are ALV003, an enzyme combination of 2 enzymes that is currently undergoing FDA testing, AN-PEP, produced by DSM, and enzyme that was originally used to make cold brewed beer clear, and a product called KumaMax, purchased by Takeda Pharmaceuticals. At this time only AN-PEP is available in various concentrations on the market. It has been particularly effective at breaking down gluten at a low pH commonly found in the stomach, and a study has shown that AN-PEP is even more effective if combined with a food grade acid. The tests were done in healthy volunteers and under laboratory conditions and several groups of researchers came to the same conclusions that AN-PEP is very effective in cleaving the gliadin molecule. The tests are considered pertinent even if healthy volunteers were selected because enzymes work in the stomach and not systemically and in that respect, there is no difference between a celiac patient and a healthy individual.  
    Until a few years ago, gluten-sensitivity was considered to have the same cause as celiac disease, namely the gliadin molecule and in order to avoid regulator issues, these enzymes were recommended only for gluten sensitivity but not for celiac disease. Recent work suggests that these enzymes are in fact not as effective for gluten sensitivity because the culprit of most gluten sensitivities might not be the gliadin molecule. 
    Enzymes Do Not Change the Nature of Celiac Disease and Do Not Treat or Cure It
    Existing data is very encouraging and clearly proves that AN-PEP enzymes greatly reduce the concentration of gliadin and can possibly even make it undetectable. It is important to note, that these enzymes do not change the nature of celiac disease and therefore do not treat or cure it. They can only break down the molecule that is triggering a reaction and therefore help maintain a gluten-free diet when contaminants are present. Essentially, there are two ways to maintain a gluten-free diet. One way is to avoid any contaminants in the food but most authorities agree that this is almost unattainable. The second way, is to break down the contaminants before they can cause damage. The underlying immune-deficiency is not changed and adherence to a gluten-free diet can not be neglected. Clinicians are reluctant to recommend enzymes for gluten contamination and certainly not for intentional consumption without regulatory approval. 
    The big challenge is that short term gluten challenge studies have been inconclusive because they did not prove an advantage over a placebo. In order to obtain conclusive results, patients who have been on a gluten-free diet for months or even for years before they develop symptoms or antibodies, and therefore a study to prove conclusively an advantage over a placebo, is very difficult to conduct and might take years. Given this challenge, it is unlikely that an enzyme will ever go through the FDA process. As long as enzymes are not recommended to treat or cure a disease, they do not have to be FDA approved but are regulated by the FDA and have to be registered as dietary ingredients. 
    Enzymes Could Lead to Being Less Careful and Cause a Higher Risk of Gluten Exposure
    There is the concern that enzymes could lead to being less careful and therefore causing a higher risk of gluten exposure, and this is a valid argument, but the ethical question then arises whether this is enough reason to withhold the additional benefit of safety to those who are careful.
    A recent study suggests that there is a method to measure the impact of gluten with a blood test of interleukin-2 within a few hours of gluten ingestion, and the results could make a gluten-challenge study shorter and safer and could help investigate enzymes or other methods that support a gluten-free diet.
    Another very promising application for enzymes is to treat gluten-containing food products and break down the immunogenic components of gliadin. These foods could not be labeled as gluten-free but only as gluten-removed. It is currently accepted that alcoholic drinks such as vodka or whiskey that are made from gluten containing grains are considered safe because of the distillation process that removes all gluten-proteins from the final product. Current laboratory tests are very accurate in determining if a product does or does not contain gluten. Currently an enzymatically treated product is not considered at the same level of safety as when gluten (gliadin molecule) is completely removed from a food product. However, at least theoretically, there should be no difference between a product that is made from non-gluten containing ingredients and a product that has been treated in a way that the finished product has no detectable gluten molecules. 
    In conclusion, evidence is very strong that enzymes could be recommended for the breakdown of contaminants in support of a gluten-free diet, but not to replace a gluten-free diet. This does greatly enhance the quality of life for celiac patients when eating outside of a completely controlled environment, which is not attainable for most people. 
    Join the forum discussion on on enzymes discussed in this article.
    Studies on AN-PEP:
    Extra-Intestinal Manifestation of Celiac Disease in Children. Nutrients 2018, 10(6), 755; doi:10.3390/nu10060755 Efficient degradation of gluten by a prolyl endoprotease in a gastrointestinal model Enzymatic gluten detoxification: the proof of the pudding is in the eating! Highly efficient gluten degradation with a newly identified prolyl endoprotease: implications for celiac disease Degradation of gluten in wheat bran and bread drink by means of a proline-specific peptidase References:
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