BL-7010 Demonstrates Specific Binding to Gliadin and Reduces Gluten-Associated Pathology in a Chronic Mouse Model of Gliadin Sensitivity
- Journal Article
Rights / licenseCreative Commons Attribution 4.0 International
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. Show more
Journal / seriesPLoS ONE
Pages / Article No.
PublisherPublic Library of Science
SubjectAUTOIMMUNKRANKHEITEN (PATHOLOGIE); GLUTEN + KLEBERPROTEINE (LEBENSMITTELINDUSTRIE); PROLAMINE (PROTEINE, PEPTIDE); COPOLYMERISATE (KUNSTSTOFFE); TIERISCHE MODELLE IN DER MEDIZIN; TIERVERSUCHE (TOXIKOLOGISCHE UNTERSUCHUNGEN); IN-VITRO UNTERSUCHUNGEN (TOXIKOLOGIE); AUTOIMMUNE DISEASES (PATHOLOGY); GLUTEN + GLUTEN PROTEINS (FOOD INDUSTRY); PROLAMINS (PROTEINS AND PEPTIDES); COPOLYMERS (PLASTICS); ANIMAL MODELS IN MEDICINE; ANIMAL EXPERIMENTS (TOXICOLOGICAL INVESTIGATIONS); IN VITRO STUDIES (TOXICOLOGY)
Organisational unit02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.
03811 - Leroux, Jean-Christophe / Leroux, Jean-Christophe
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