naa a22 4500 528783602 20180924065515.0 cr unu---uuuuu 180924e20141103xx s 000 0 eng 10.3929/ethz-a-010346285 doi 10.1371/journal.pone.0109972 doi (ETHRESEARCH)oai:www.research-collection.ethz.ch:20.500.11850/281618 BL-7010 Demonstrates Specific Binding to Gliadin and Reduces Gluten-Associated Pathology in a Chronic Mouse Model of Gliadin Sensitivity [Elektronische Daten] [Justin L. McCarville, Yotam Nisemblat, Heather J. Galipeau, Jennifer Jury, Rinat Tabakman, Ad Cohen, Esmira Naftali, Bela Neiman, Efrat Halbfinger, Joseph A. Murray, Arivarasu N. Anbazhagan, Pradeep K. Dudeja, Alexander Varvak, Jean-Christophe Leroux, Elena F. Verdu] PLoS ONE Open access ethresearch Celiac disease (CD) is an autoimmune disorder in individuals that carry DQ2 or DQ8 MHC class II haplotypes, triggered by the ingestion of gluten. There is no current treatment other than a gluten-free diet (GFD). We have previously shown that the BL-7010 copolymer poly(hydroxyethyl methacrylate-co-styrene sulfonate) (P(HEMA-co-SS)) binds with higher efficiency to gliadin than to other proteins present in the small intestine, ameliorating gliadin-induced pathology in the HLA-HCD4/DQ8 model of gluten sensitivity. The aim of this study was to investigate the efficiency of two batches of BL-7010 to interact with gliadin, essential vitamins and digestive enzymes not previously tested, and to assess the ability of the copolymer to reduce gluten-associated pathology using the NOD-DQ8 mouse model, which exhibits more significant small intestinal damage when challenged with gluten than HCD4/DQ8 mice. In addition, the safety and systemic exposure of BL-7010 was evaluated in vivo (in rats) and in vitro (genetic toxicity studies). In vitro binding data showed that BL-7010 interacted with high affinity with gliadin and that BL-7010 had no interaction with the tested vitamins and digestive enzymes. BL-7010 was effective at preventing gluten-induced decreases in villus-to-crypt ratios, intraepithelial lymphocytosis and alterations in paracellular permeability and putative anion transporter-1 mRNA expression in the small intestine. In rats, BL-7010 was well-tolerated and safe following 14 days of daily repeated administration of 3000 mg/kg. BL-7010 did not exhibit any mutagenic effect in the genetic toxicity studies. Using complementary animal models and chronic gluten exposure the results demonstrate that administration of BL-7010 is effective and safe and that it is able to decrease pathology associated with gliadin sensitization warranting the progression to Phase I trials in humans. Creative Commons Attribution 4.0 International http://creativecommons.org/licenses/by/4.0 ethresearch AUTOIMMUNKRANKHEITEN (PATHOLOGIE) ethresearch GLUTEN + KLEBERPROTEINE (LEBENSMITTELINDUSTRIE) ethresearch PROLAMINE (PROTEINE, PEPTIDE) ethresearch COPOLYMERISATE (KUNSTSTOFFE) ethresearch TIERISCHE MODELLE IN DER MEDIZIN ethresearch TIERVERSUCHE (TOXIKOLOGISCHE UNTERSUCHUNGEN) ethresearch IN-VITRO UNTERSUCHUNGEN (TOXIKOLOGIE) ethresearch AUTOIMMUNE DISEASES (PATHOLOGY) ethresearch GLUTEN + GLUTEN PROTEINS (FOOD INDUSTRY) ethresearch PROLAMINS (PROTEINS AND PEPTIDES) ethresearch COPOLYMERS (PLASTICS) ethresearch ANIMAL MODELS IN MEDICINE ethresearch ANIMAL EXPERIMENTS (TOXICOLOGICAL INVESTIGATIONS) ethresearch IN VITRO STUDIES (TOXICOLOGY) ethresearch Life sciences ethresearch Medical sciences, medicine ethresearch McCarville Justin L. joint author Nisemblat Yotam joint author Galipeau Heather J. joint author Jury Jennifer joint author Tabakman Rinat joint author Cohen Ad joint author Naftali Esmira joint author Neiman Bela joint author Halbfinger Efrat joint author Murray Joseph A. joint author Anbazhagan Arivarasu N. joint author Dudeja Pradeep K. joint author Varvak Alexander joint author Leroux Jean-Christophe joint author Verdu Elena F. joint author PLoS ONE San Francisco, CA : Public Library of Science 9 (11), p. e109972 1932-6203 http://hdl.handle.net/20.500.11850/281618 text/html WWW-Backlink auf das Repository (Open access) 1 Journal Article ethresearch ETHRESEARCH 856 40 http://hdl.handle.net/20.500.11850/281618 text/html WWW-Backlink auf das Repository (Open access) ETHRESEARCH 700 1- McCarville Justin L. joint author ETHRESEARCH 700 1- Nisemblat Yotam joint author ETHRESEARCH 700 1- Galipeau Heather J. joint author ETHRESEARCH 700 1- Jury Jennifer joint author ETHRESEARCH 700 1- Tabakman Rinat joint author ETHRESEARCH 700 1- Cohen Ad joint author ETHRESEARCH 700 1- Naftali Esmira joint author ETHRESEARCH 700 1- Neiman Bela joint author ETHRESEARCH 700 1- Halbfinger Efrat joint author ETHRESEARCH 700 1- Murray Joseph A. joint author ETHRESEARCH 700 1- Anbazhagan Arivarasu N. joint author ETHRESEARCH 700 1- Dudeja Pradeep K. joint author ETHRESEARCH 700 1- Varvak Alexander joint author ETHRESEARCH 700 1- Leroux Jean-Christophe joint author ETHRESEARCH 700 1- Verdu Elena F. joint author ETHRESEARCH 773 0- PLoS ONE San Francisco, CA : Public Library of Science 9 (11), p. e109972 1932-6203 BK010053 XK010053 XK010000 ETHRESEARCH ETHRESEARCH ETHRESEARCH Journal Article Open access