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Showing results for tags 'nanoparticle'.
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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 sciencedaily.com
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“Tight junction function” might sound like a song from Schoolhouse Rock, but it’s a topic that explains a great deal about our immune system and the increasing prevalence of autoimmune disorders. The tight junction (TJ) is an essential element of our intestinal structure, and is part of the body’s defenses against bacteria and toxins. About 70% of the body’s immune system resides in the gut, mostly as lymphatic cells. To prevent the immune system from being overtaxed, the TJ restricts access to these cells. The TJ is a matrix of interlocking proteins that open and close tiny pores between cells. The proteins form a hexagonal pattern, similar to chicken wire. Substances can pass through the intestinal wall, either through cell membranes, or between cells, using a the pores (gaps in the chicken wire). Pores help the body absorb nutrients, but must be selective. They use an electrostatic charge to filter out large particles, and to bind cells close together. Zonulins are messenger proteins that signal the pores to open. When zonulins are released, they bind to specific chemical receptors in the intestinal wall. These receptors tell the body to add a phosphoryl group to one of the proteins in the matrix. This deactivates the protein, disassembling the TJ’s hexagonal structure (like cutting a strand of the chicken wire.) The lymphatic cells address molecules that pass through the TJ, and may mark them as antigens (dangerous substances). The “danger” flag may go up on molecules larger in size than the normal dimension of the pores (typical of bacterial infections), known toxins, or a sudden flood of material that is new to the lymphatic cells in the gut. The immune system remembers each antigen and attacks it when it reappears. While this is an effective way to keep out bacteria and toxins, the problem is overkill. When the TJ is leaky (TJ dysfunction is also known as “leaky gut”), the body attacks all substances marked as antigens, even otherwise benign foods. This stresses the immune system, creating inflammation. Inflammation damages the TJ further, loosening it to admit new substances. This creates a vicious cycle, making the TJ even more permeable. This explains why Celiacs who recently had a gluten exposure tend to become sensitive to other foods they are eating during the time they are suffering from leaky gut. Those foods are passing through the loosened pores, and being marked as antigens. But why do the TJs fail to begin with? Everyone releases some zonulin in response to gluten, but those with a gene for Celiac disease release far more zonulin (two standard deviations above the norm, well beyond coincidence). Bacterial infections can also trigger zonulin release. Some industrial food additives are also zonulin triggers. They include nanoparticles (such as titanium dioxide – check your toothpaste and chewing gum ingredients), microbial transglutaminase (“meat glue”), salt nanowires, organic solvents, and emulsifiers. These new ingredients are increasingly common in the U.S. food supply. If they sound inscrutable, it’s for good reason; they’re not naturally occurring. Elevated zonulin levels and TJ permeability are associated with Celiac disease and Type 1 Diabetes. (A drug that reduces zonulin production also protects against damage to insulin-producing cells in Type 1 Diabetes patients.) Overproduction of zonulin is also found in those with Crohn’s disease, schizophrenia, and chronic kidney disease, and other disorders. The intestinal tight junction, and damage to it, is strongly associated with various autoimmune diseases. We are just beginning to understand the role of this important system in modulating health, and the factors that cause it to fail. Sources Anderson, J.M., and C.M. Van Itallie. (2009). Physiology and function of the tight junction. Cold Spring Harb Perspect Biol; 1:a002584. doi: 10.1101/cshperspect.a002584 Brandner, J.M., M. Zorn-Kruppa, T. Yoshida, I. Moll, L.A. Beck, and A. De Benedetto. (2015). Epidermal tight junctions in health and disease. Tissue Barriers 3:1-2, e974451; January-June 2015. doi: 10.4161/21688370.2014.974451 Fassiano, A. (2012). Zonulin, regulation of tight junctions, and autoimmune diseases. Ann N Y Acad Sci. 2012 July; 1258(1): 25–33. doi:10.1111/j.1749-6632.2012.06538.x Khaleghi, S., J.M. Ju, A. Lamba and J.A. Murray. (2016). The potential utility of tight junction regulation in celiac disease: focus on larazotide acetate. Ther Adv Gastroenterol 9(1): 37–49. doi: 10.1177/1756283X15616576 Lerner, A., and T. Matthias. (2015). Changes in intestinal tight junction permeability associated with industrial food additives explain the rising incidence of autoimmune disease. Autoimmunity Reviews 14 (2015) 479–489. doi:10.1016/j.autrev.2015.01.009 Vighi, G., F. Marcucci, L. Sensi, G. Di Cara, and F. Frati. (2008). Allergy and the gastrointestinal system. Clinical and Experimental Immunology, 153 (Suppl. 1): 3–6. doi:10.1111/j.1365-2249.2008.03713.x
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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
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