Search the Community

Celiac.com 06/02/2014 - Despite following a gluten-free diet, many people with celiac disease continue to have symptoms, and to suffer from ongoing small intestinal inflammation. Can a drug be created to alleviate such symptoms and inflammation, and protect celiacs on a gluten-free diet against small amounts of gluten contamination? San Carlos California-based Alvine Pharmaceuticals is conducting a phase 2 trial to determine whether their drug, ALV003, an orally administered mixture of 2 recombinant gluten-specific proteases can protect celiac disease patients from gluten-induced mucosal damage. For this trial, Alvine is working with researchers Marja-Leena Lähdeaho, Katri Kaukinen, Kaija Laurila, Pekka Vuotikka, Olli-Pekka Koivurova, Tiina Kärjä-Lahdensuu, Annette Marcantonio, Daniel C. Adelman, and Markku Mäki. They are affiliated with the School of Medicine and Tampere University Hospital at the University of Tampere; the Department of Gastroenterology and Alimentary Tract Surgery at Tampere University Hospital and School of Medicine at the University of Tampere, and FinnMedi Oy in Tampere, Finland; the Department of Medicine at Seinäjoki Central Hospital in Seinäjoki, Finland; Liikuntaklinikka, Oulu Diakonissalaitos; and Terveys, Oulu Diakonissalaitos, Oulu, Finland. For their Phase 2 trial, the research team first established two grams of gluten per day as the optimal challenge dose for their 6-week gluten study. They then randomly assigned 20 adults with biopsy-proven celiac disease to receive ALV003, and twenty-one to receive a placebo. Both groups also received 2 grams of gluten each day. The team conducted duodenal biopsies at baseline, and after gluten challenge, focusing on the ratio of villus height to crypt depth and densities of intraepithelial lymphocytes. A total of seven patients dropped out due to adverse reactions. Four were receiving ALV003, and three were receiving the placebo. Sixteen patients given ALV003 and 18 given placebo were eligible for efficacy evaluation. Biopsies from subjects in the placebo group showed evidence of mucosal injury after gluten challenge, with average villus height to crypt depth ratio changed from 2.8 before challenge to 2.0 afterward. (P = .0007; density of CD3þ intraepithelial lymphocytes changed from 61 to 91 cells/mm after challenge; P = .0003). However, the team saw no significant mucosal deterioration in biopsies from the ALV003 group. The two groups showed no significant differences in symptoms, though they did show substantial differences in morphologic changes, and CD3þ intraepithelial lymphocyte counts differed significantly from baseline to week 6 (P = .0133 and P = .0123, respectively). This small, but important, step means that ALV003 did provide significant protection against gluten-induced gut damage for people with celiac disease on an otherwise gluten-free diet, which means that Alvine can continue to the next phases in the development process. If successful, glutenase ALV003 will be the first drug to protect people with celiac disease against gut damage from small amounts of gluten. Source: Clinicaltrial.gov, Numbers: NCT00959114 and NCT0125569

Celiac.com 04/29/2020 - People with celiac disease cannot eat gluten from products made with wheat, barley or rye. The two main culprits proteins in gluten are glutenin and gliadin, with the latter thought to cause most of the inflammation and adverse health health effects in people with celiac disease. Glutenases are enzymes needed to break down glutens in foods to make these foods easier for people to digest. Imagine an enzyme that could be added to traditional wheat or gluten-containing products to make them gluten-free. The technology would work very much the way adding lactase to regular milk breaks down the lactose proteins and makes the milk safe for people with milk intolerance. It's a very cool idea. One major hurdle involves the fact that glutenase enzymes that break down gluten proteins can't take the high temperatures used to manufacture or process food. Researchers Seek Enzymes to Break Down Gluten in Food Production A team of researchers at Clemson University may have solved that problem, or all least made strong progress. Sachin Rustgi, an assistant professor of molecular breeding in Clemson’s Advanced Plant Technology Program, is working with numerous other to create glutenases capable of withstand high cooking temperatures. In addition to Rustgi, others involved in the study are: Claudia Osorio, Nuan Wen, Diter von Wettstein and Shannon Mitchell of Washington State University, and Jaime H. Mejías of Institute of Agricultural Research (INIA), Chile. Early results from their study show that it's possible to create glutenase enzymes that can handle the high temperatures required to manufacture or process foods. However promising, the results are merely preliminary, and further study will be needed before the full results will be known. Such an enzyme might allow manufacturers to add glutenases to food labeled ‘gluten-free’” Rustgi said. “This will allow people with celiac disease to tolerate foods that are contaminated with gluten/wheat." Alternatively, such an enzyme could allow researchers to engineer wheat grains that incorporates such glutenases into its structure. "After necessary testing, this may provide an alternative treatment for celiac disease,” Rustgi said. Imagine traditional bread that was gluten-free and made safe to eat through the addition of enzymes. Few things would be more promising to people with celiac disease. Stay tuned for more on the efforts to develop enzymes that can break down gluten, and potentially help people with celiac disease to avoid damage from accidental gluten-ingestion. Read more at Newsstand.clemson.edu

Celiac.com 07/27/2020 - Immunogenic gluten peptides that resist gastrointestinal breakdown are the main triggers for celiac disease. Gluten degrading enzymes represent a promising treatment option for managing celiac disease, but need to meet certain conditions within the gut to render gluten harmless before it reaches the duodenum. A team of researchers recently set out to review oral, gluten-degrading enzymes meant for use by celiacs on a gluten-free diet, discussing their origin and activities, their clinical evaluation and challenges for therapeutic application. The research team included Guoxian Wei, Eva J Helmerhorst, Ghassan Darwish, Gabriel Blumenkranz, and Detlef Schuppan. They are variously affiliated with the Department of Molecular and Cell Biology, Henry M. Goldman School of Dental Medicine, Boston, MA, USA; the Institute for Translational Immunology and Research Center for Immunotherapy (FZI), Johannes Gutenberg University (JGU) Medical Center in Mainz, Germany; and the Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Most people with celiac disease are exposed to trace amounts of gluten on a regular basis. Whether due to high sensitivity or repeated exposure, many celiac patients continue to suffer both symptoms and damage despite following a gluten-free diet. In addition to simplified testing for ongoing gluten-exposure, there's a pressing need for safe treatments that can help address the realities of gluten-exposure by those on a gluten-free diet. Gluten-degrading enzymes are one especially promising option. To be effective, such enzymes would need to be safe for people, active under gastro-duodenal conditions, and rapidly neutralizing T cell activating gluten peptides. Gluten peptides normally resist digestion, but a number of enzymes, including bacterial, fungal and plant derived glutenases, especially food-grade subtilisins (Sub-A), prolyl endopeptidases (PEP), AN-PEP enzymes, barley seed derived glutamine-specific cysteine endoprotease (EP-B2) and synthetic glutenases (Kuma030) are all potential game changers for oral enzyme therapy for people with celiac disease. Researchers have had some success with various combinations of enzymes, molecular modeling and chemical modifications, such as PEGylation, enteric coatings or enzyme carriers. The goal is to develop a product that can quickly and completely break down immunogenic gluten peptides that are bound up in foods. The digestion of gluten peptides must happen fully within the stomach and proximal small intestine before these peptides reach the mucosal immune system of the small intestine. Without exception, these enzymes must function in the glutamine- and proline-rich environments of antigenic gluten peptides. Such enzymes also need to remain stable in stomach acid, and in the near neutral pH in the duodenum. According to the researchers: "Bacterial, fungal and plant derived glutenases, especially (food-grade) subtilisins (Sub-A), prolyl endopeptidases (PEP), barley seed derived glutamine-specific cysteine endoprotease (EP-B2) and synthetic glutenases (Kuma030) are considered promising candidates for an (adjunctive) oral enzyme therapy. " The team's recent review acknowledges the potential for oral enzymes in improving celiac disease treatment, and focuses on the origins and actions, clinical evaluations and therapeutic challenges faced by enzymes intended to treat celiac disease. Read more at: MDPI.com